WO2004051229A1 - Liquid switch, and microchip and mass-analyzing system using the same - Google Patents

Liquid switch, and microchip and mass-analyzing system using the same Download PDF

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Publication number
WO2004051229A1
WO2004051229A1 PCT/JP2003/015416 JP0315416W WO2004051229A1 WO 2004051229 A1 WO2004051229 A1 WO 2004051229A1 JP 0315416 W JP0315416 W JP 0315416W WO 2004051229 A1 WO2004051229 A1 WO 2004051229A1
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WO
WIPO (PCT)
Prior art keywords
liquid
flow path
sample
switch
liquid switch
Prior art date
Application number
PCT/JP2003/015416
Other languages
French (fr)
Japanese (ja)
Inventor
Kazuhiro Iida
Masakazu Baba
Hisao Kawaura
Toru Sano
Noriyuki Iguchi
Hiroko Someya
Wataru Hattori
Minoru Asogawa
Original Assignee
Nec Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nec Corporation filed Critical Nec Corporation
Priority to JP2004556888A priority Critical patent/JPWO2004051229A1/en
Priority to US10/537,295 priority patent/US7274016B2/en
Priority to CA 2508456 priority patent/CA2508456A1/en
Publication of WO2004051229A1 publication Critical patent/WO2004051229A1/en

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • HELECTRICITY
    • H01ELECTRIC ELEMENTS
    • H01JELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00Particle spectrometers or separator tubes
    • H01J49/02Details
    • H01J49/04Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06Fluid handling related problems
    • B01L2200/0621Control of the sequence of chambers filled or emptied
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/06Valves, specific forms thereof
    • B01L2400/0688Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • G01N30/04Preparation or injection of sample to be analysed
    • G01N30/16Injection
    • G01N30/20Injection using a sampling valve
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T137/00Fluid handling
    • Y10T137/4891With holder for solid, flaky or pulverized material to be dissolved or entrained

Definitions

  • the present invention relates to a liquid switch for controlling the flow of a liquid, a microphone chip using the same, and a mass spectrometry system.
  • microchemical analysis in which chemical operations such as sample pretreatment, reaction, separation, and detection are performed on a microchip, is rapidly developing. According to the microphone mouth chemical analysis, only a small amount of sample is required, and the environmental load is small and highly sensitive analysis is possible.
  • Patent Document 1 describes an apparatus that realizes capillary electrophoresis using a microchannel type chip having a configuration in which a groove and a reservoir are provided on a substrate.
  • this type of microchip it is important to precisely control the timing at which the sample / buffer is introduced into the flow path in the chip.
  • Such techniques are required not only in separation devices and analysis devices, but also in microchemical reaction devices.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2000-200703 Disclosure of Invention
  • the present invention has been made in view of the above circumstances, and in a device such as a microchip, the flow of a liquid such as a sample or a buffer is precisely controlled to separate, analyze, or react a sample. It is an object of the present invention to provide a switch structure which can be controlled under desired conditions with good controllability. Another object of the present invention is to provide a switch structure that enables a plurality of processes to be activated at an appropriate timing by capillary force, triggered by one sample injection, without the aid of an external control device. It is in.
  • a flow path through which the first liquid passes, a damming portion provided in the flow passage, which dams the first liquid, and a downstream portion of the damming portion, And a trigger flow passage communicating with the flow passage and guiding the second liquid to the damming portion.
  • the first liquid is blocked at the blocking section.
  • the blocking unit may be configured to absorb and retain the first liquid, or the blocking unit itself exhibits lyophobicity to the first liquid, and the first liquid is provided at the upstream end thereof.
  • a configuration in which the body is blocked may be used.
  • the liquid sample blocked by the blocking unit flows out downstream of the blocking unit when coming into contact with the second liquid.
  • opening of a flow path can be performed with desired controllability at a desired timing by introducing a 2nd liquid, without providing an external control apparatus.
  • the damming portion may be configured to include a member that holds the first liquid.
  • the second liquid when the second liquid is introduced into the flow path, the liquid surface of the first liquid and the liquid surface of the second liquid held by the member come into contact with each other. Then, the first liquid flows out downstream of the damming portion. In this way, it is possible to open the flow path at a desired timing with good controllability.
  • the flow passage surface area per unit volume of the flow passage in the damming portion is larger than the flow passage surface area per unit volume of the flow passage in the other part of the flow passage.
  • a structure configured so that This is because a capillary force is generated and a liquid retention effect is exhibited. Specific examples of such a structure include a plurality of particles, a porous body, a structure including a plurality of spaced apart protrusions, and the like.
  • the damming portion may be configured to include a region that is lyophobic to the first liquid.
  • the lyophobic area is lyophobic to the first liquid It can be obtained by a method in which a flow path is formed using a surface of a substrate having a property and utilizing the surface, or a method in which the surface of the flow path is treated with such a compound.
  • a degree of lyophobicity By adjusting the degree of lyophobicity, a smooth transition to the open state and a smooth flow state after the open state can be realized.
  • a valve structure may be provided in the trigger passage, and when a predetermined amount of the second liquid is introduced, the valve structure may be operated to close the one trigger passage. By doing so, it is possible to introduce only a predetermined amount of the second liquid.
  • the second liquid introduced from the trigger channel is maintained in a band-like form, so that a sample suitable for, for example, separating components can be provided.
  • a band-shaped sample suitable for separation operation can be stably introduced. .
  • the present invention has a flow path through which a liquid passes, and a damming portion provided in the flow passage to dam the liquid, wherein the damming portion includes a member holding the liquid.
  • a liquid switch is provided.
  • the switch can be switched to the open state by applying vibration, or by dropping a predetermined liquid substance on the damming portion.
  • the member holding the liquid was configured such that the flow path surface area per unit volume of the flow path in the damming portion was larger than the flow path surface area per unit volume of the flow path in the other part of the flow path.
  • Structure This is because a capillary force is generated and a liquid retaining action is generated.
  • Specific examples of such a structure include a plurality of particles, a porous body, a plurality of protrusions spaced apart, and the like.
  • the present invention has a flow path through which a liquid passes, and a damming portion provided in the flow passage to dam the liquid. And a liquid switch comprising a lyophobic surface.
  • the switch can be switched to the open state by applying vibration or by dropping a predetermined liquid substance into the damming portion.
  • the lyophobic region can be obtained by a method of forming a flow channel using the surface of a substrate that is lyophobic to the above liquid, or by treating the surface of the flow channel with such a compound. .
  • a smooth transition to the open state and a smooth flow state after the open state can be realized.
  • the moving member further includes a moving member disposed in the flow path to be movable from the damming portion to a position other than the damming portion. It may have a surface that shows lyophilicity for one liquid, so that the position of the moving member can be adjusted from outside the channel.
  • the switch when the moving member is outside the region showing the lyophobicity, the switch is in a closed state.
  • the moving member is located in the region exhibiting the lyophobicity, the passage along the surface of the moving material becomes the first liquid flow path, and the flow path is opened.
  • a position adjusting means for adjusting the position of the moving member from the outside may be further provided, and one of the moving member and the position adjusting means may be a magnet and the other may be a magnetic material. By doing so, the position of the moving member can be adjusted from the outside.
  • a flow path through which the first liquid passes a sub flow path communicating with the flow path, a chamber communicating with the sub flow path, a communication path with the chamber, and a second flow path in the chamber
  • a trigger flow path for introducing a liquid; and a lyophobic substance showing lyophobicity with respect to the first liquid is stored inside the chamber, and a second liquid is supplied from the trigger flow path.
  • a liquid switch is provided, wherein the liquid switch is configured to introduce the lyophobic substance from the chamber to the flow path when introduced.
  • the chamber is interposed between a first chamber communicating with the sub-flow path, a second chamber storing the lyophobic substance, and the first and second chambers.
  • the second small chamber for storing the lyophobic substance has a structure not communicating with the sub flow path.
  • the lyophobic substance may be a liquid or a gas, and may be air or the like.
  • the liquid switch is configured such that a lyophobic substance is introduced into a flow path through which the first liquid flows when the second liquid serving as a trigger is introduced, and the flow path is closed.
  • a lyophobic substance is introduced into a flow path through which the first liquid flows when the second liquid serving as a trigger is introduced, and the flow path is closed.
  • a substrate a sample flow path through which a sample formed on the substrate passes, and a sample separation unit provided in the sample flow path, wherein the sample flow path described above is provided in the sample flow path.
  • a microchip is provided, wherein a liquid switch is provided, and the supply of the sample from the sample channel to the sample separation unit is controlled by the liquid switch.
  • a substrate a liquid flow path formed on the substrate, through which a liquid passes, and a reaction unit provided in the liquid flow path.
  • a microchip is provided, wherein a switch is provided, and supply of liquid from the liquid flow path to the reaction section is controlled by the liquid switch.
  • the microchip further includes a reservoir that communicates with the reaction section and into which a reagent is introduced.
  • the liquid switch is disposed in a liquid flow path from the reservoir to the reaction section, and the liquid switch is provided from the reservoir.
  • the introduction of the reagent into the section may be controlled by the liquid switch.
  • the reagent can be, for example, an enzyme digestion solution such as a trypsin digestion solution.
  • a substrate a main flow path through which a liquid formed on the substrate passes, a clock flow path that controls a timing at which the liquid passes through a predetermined portion of the main flow path, and a main flow path and a clock
  • Microchips are provided. According to the present invention, various processes such as a separation operation and a reaction performed on a chip can be executed with good time controllability by using a clock channel.
  • microchips can perform sample separation and reaction under desired conditions with good controllability using a liquid switch.
  • liquid mixing, reaction, separation, and the like can be performed at an appropriate timing according to a predetermined schedule.
  • a separation means for separating a biological sample according to a molecular size or a property, a pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means,
  • a mass spectrometry system comprising: drying means for drying the processed sample; and mass spectrometry means for mass analyzing the dried sample, wherein the separation means includes the microchip described above.
  • a separation means for separating a biological sample according to a molecular size or a property
  • a pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means
  • a mass spectrometry system comprising: drying means for drying the processed sample; mass spectrometry means for mass analyzing the dried sample; wherein the pretreatment means includes the microchip described above. It is.
  • a separation means for separating a biological sample according to a molecular size or a property, a pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means, A drying unit for drying the processed sample; and a mass analysis unit for mass analyzing the dried sample, wherein the separation unit, the pretreatment unit, or the drying unit includes the microchip described above.
  • the flow of a liquid such as a sample or a buffer is precisely controlled to separate, analyze, or A switch structure for performing a reaction under desired conditions with good controllability is provided.
  • FIG. 1 is a diagram illustrating a switch structure according to an embodiment.
  • FIG. 2 is a diagram illustrating a structure of a damming portion included in the switch structure according to the embodiment.
  • FIG. 3 is a diagram showing a valve structure for holding a trigger liquid in the switch structure according to the embodiment.
  • FIG. 4 is a diagram illustrating a switch structure according to the embodiment.
  • FIG. 5 is a diagram showing a cross-sectional structure of the switch according to the embodiment.
  • FIG. 6 is a diagram showing a structure of the separation device according to the embodiment.
  • FIG. 7 is a diagram showing a switch structure according to the embodiment.
  • FIG. 8 is a diagram showing a structure of a damming portion included in the switch structure according to the embodiment.
  • FIG. 9 is a diagram showing the structure of the microchemical reaction device according to the embodiment.
  • FIG. 10 is a diagram showing the structure of the device according to the embodiment.
  • FIG. 11 is a diagram showing a switch structure according to the embodiment.
  • FIG. 12 is a diagram showing a switch structure according to the embodiment.
  • FIG. 13 is a diagram showing a switch structure according to the embodiment.
  • FIG. 14 is a diagram showing the structure of the chip according to the embodiment.
  • FIG. 15 is a diagram showing a switch structure according to the embodiment.
  • FIG. 16 is a schematic diagram showing the configuration of the mass spectrometer.
  • Figure 17 is a block diagram of the mass spectrometry system.
  • FIG. 18 is a diagram showing a switch structure according to the embodiment.
  • FIG. 19 is a diagram showing a switch structure according to the embodiment.
  • FIG. 20 is a diagram showing a switch structure according to the embodiment.
  • FIG. 21 is a diagram illustrating the structure of the switch according to the embodiment.
  • FIG. 22 is a diagram for explaining the operation of the switch according to the embodiment.
  • FIG. 23 is a diagram illustrating the structure of the switch according to the embodiment.
  • FIG. 24 is a diagram for explaining the operation of the switch according to the embodiment.
  • FIG. 25 is a diagram for explaining the operation of the switch according to the embodiment.
  • FIG. 26 is a diagram for explaining the operation of the switch according to the embodiment.
  • FIG. 27 is a diagram for explaining the operation of the switch according to the embodiment.
  • FIG. 27 is a diagram for explaining the operation of the switch according to the embodiment.
  • the switch described in each embodiment is used for controlling a liquid moving in a flow path in a microchip having a flow path and a reservoir on a substrate.
  • the liquid to be introduced is an aqueous solution unless otherwise specified.
  • a quartz substrate is used as a substrate, but a plastic material, silicon, or the like may be used as another substrate material.
  • the plastic material include thermoplastic resins such as silicone resin, PMMA (polymethyl methacrylate), PET (polyethylene terephthalate), and PC (polycarbonate), and thermosetting resins such as epoxy resin. . Such a material is easy to mold and can reduce the manufacturing cost.
  • a method for forming a portion of the microchip such as a flow path and a reservoir
  • a method combining photolithography and etching can be cited, but when a plastic material is used as a substrate material, injection molding, A method such as hot embossing can be adopted.
  • FIG. 1 is a top view of the liquid switch.
  • FIG. 1 (a) shows the switch in a closed state
  • FIGS. 1 (b) and 1 (c) show the switch in an open state.
  • a single trigger channel 102 is connected to a side surface of the main channel 101.
  • the traveling speed of the liquid in the flow path can be adjusted by appropriately adjusting the degree of hydrophilicity in the flow path, the flow path diameter, and the like. Thereby, the speed of the switch operation can be adjusted.
  • a damming portion 105 is provided on the upstream side (left side in the figure) of the area where the main flow path 101 and the trigger flow path 102 intersect.
  • the blocking portion 105 is a portion having a stronger capillary force than other portions of the flow path. The following is an example of a specific configuration of the blocking unit 105.
  • the flow channel surface area per unit volume of the flow channel in the damming portion 105 is larger than that of the other portion of the flow channel. That is, when the main flow path 101 is filled with liquid, the flow path damming portion 105 is configured to have a larger surface area and a larger solid-liquid interface than the other parts of the flow path. . (i i) Configuration filled with multiple porous bodies and beads
  • the surface of the flow passage blocking portion 105 is configured to have a larger surface area and a larger solid-liquid interface than the other portions of the flow passage.
  • the columnar body can be formed by an appropriate method according to the type of the substrate.
  • a quartz substrate or a quartz substrate it can be formed using a photolithography technique and a dry etching technique.
  • a plastic substrate is used, a mold having an inverted pattern of the pattern of the pillar to be formed is manufactured, and molding is performed using the mold to obtain a desired pillar pattern surface.
  • a mold is used for photolithography. It can be formed by utilizing the etching technology and the dry etching technology.
  • the porous body and beads can be formed by directly filling and adhering them to predetermined locations in the flow channel.
  • FIG. 2 is a top view of the blocking unit 105.
  • the plurality of pillars 1 2 1 are regularly arranged at substantially equal intervals.
  • the area other than the columnar body 1 2 1 is a fine channel 1 2 2.
  • the flow channel surface area per unit volume of the flow channel is larger than that of other portions of the flow channel. For this reason, the liquid that has entered the damming portion 105 is retained in the fine channel 122 by capillary force.
  • FIG. 1 (a) shows the liquid switch in a standby state.
  • the liquid sample 104 introduced into the main flow path 101 is held by the damming portion 105.
  • the trigger liquid 106 is introduced at a desired timing from this state, the leading end of the liquid surface of the trigger liquid 106 advances as shown in FIG. 1 (b), and comes into contact with the damming portion 105. Will be done.
  • the liquid sample 104 is held in the damming portion 105 by capillary force, but the liquid sample 104 comes into contact with the trigger solution 106 in Fig. 1 (b).
  • the liquid sample 104 moves to the right (downstream side) in the figure, and the liquid sample 104 flows out to the downstream side of the main flow path 101 in FIG. 1 (c). That is, the trigger liquid 106 plays a role as priming water, and the operation as a liquid switch is developed.
  • the trigger liquid 106 is continuously supplied to the main flow passage 101 when the switch is in the open state.
  • control can be reliably performed by using, for example, a valve structure shown in FIG.
  • the liquid sample inflow path 130, the diverticule 131, and the liquid sample outflow path 134 are arranged in this order from the upstream side to the downstream side of the flow path. Have been.
  • a water-absorbing gel 1 3 2 is arranged in the diverticulum.
  • FIG. 3 (b) is a diagram showing a state in which the trigger one solution is introduced into the diverticulum 131, and the volume of the water-absorbing gel 132 is expanded. In this state, the fluid introduced from the upstream side of the liquid sample inflow path 130 can no longer flow out of the diverticule 13 1. That is, the water-absorbing gel 132 functions as a damming member.
  • the present embodiment relates to a switch structure using a hydrophobic region as a damming member.
  • This liquid switch can be manufactured by forming a groove on the surface of the quartz substrate. Since a quartz substrate is used, the inner wall of the groove has a hydrophilic surface.
  • the hydrophobic region can be obtained by subjecting a lid having a quartz glass surface to a hydrophobic treatment.
  • this switch is connected to the side of the main flow path 101, which is connected to the flow path 102, and the upstream main flow path 101 of the intersection area.
  • a damming section 110 is provided.
  • the main flow channel 101 and the trigger flow channel 102 except the damming portion 110 composed of a hydrophobic region are hydrophilic regions.
  • the formation of the hydrophilic region and the formation of the hydrophobic region are performed as follows. That is, after providing a covering member for covering the upper surface of the flow channel with respect to the entire flow channel of the main flow channel 101, the sample contact surface of this coating member is made hydrophobic at the damming portion 110. , And the other regions are hydrophilic.
  • FIG. 4 (a) The cross-sectional view of the flow channel shown in FIG. 4 (a) illustrates this state.
  • the covering member made of quartz glass is used as it is, and in the cross section on the right, the covering member subjected to silazane treatment is arranged with the silazane treated surface inside.
  • the liquid surface tip of the liquid sample 104 is made to stay in the area of the damming portion 110 consisting of a hydrophobic area, and the trigger one liquid 106 is formed. It is important to configure the liquid sample 104 to flow smoothly when introduced. In order to realize this, it is desirable to appropriately control the hydrophobicity of the blocking unit 110. As a method of realizing this, for example, there is a method of selecting a material to be subjected to the hydrophobic treatment of the damming portion 110 and optimizing the amount thereof. In addition, by appropriately designing the structure of the flow path, Is also possible.
  • FIG. 5 shows an example of such a structure for controlling hydrophobicity.
  • FIG. 5 shows an example of such a structure for controlling hydrophobicity.
  • FIG. 5 is a cross-sectional view of the dam unit 110 of FIG. 4 (a).
  • a plurality of fine flow paths 402 are provided in the substrate 401, and the upper surface thereof is covered with a coating material 403.
  • the microchannel 402 has a hydrophilic surface
  • the coating material 403 has a hydrophobic surface by silazane treatment.
  • the liquid holding power is determined by an appropriate balance between the water holding ability by the capillary force and the hydrophobicity of the flow channel.
  • the ratio of the ratio of the hydrophobic surface to the hydrophilic surface can be freely controlled by controlling the number and width of the microchannels 402, and as a result, the desired overall hydrophobicity is obtained. It can be controlled to a value. By controlling such a structure and controlling the surface state, the degree of hydrophobicity can be appropriately controlled.
  • Hydrophobic treatment in the present embodiment includes, for example, adhering or bonding a compound having a structure in which a unit that adsorbs or chemically bonds to a substrate material in a molecule and a unit having a hydrophobic decorative group are bonded to the substrate surface. Is realized by: As such a compound, for example, a silane coupling agent or the like can be used.
  • silane coupling agent having a hydrophobic group is hexamethine.
  • examples include those having a silazane binding group such as rudisilazane, and those having a thiol group such as 3-thiolpropyltriethoxysilane.
  • the spin coating method is a method in which a liquid in which a constituent material of a bonding layer, such as a coupling agent, is dissolved or dispersed, is applied all over a spin core. According to this method, the film thickness controllability is improved.
  • the spray method is a method of spraying a force coupling agent liquid or the like toward a substrate
  • the dipping method is a method of dipping the substrate in a coupling agent liquid or the like. According to these methods, a film can be formed by a simple process without requiring a special device.
  • the vapor phase method is a method in which a substrate is heated as necessary, and a vapor such as a cutting agent liquid is caused to flow through the substrate. Even with this method, a thin film can be formed with good film thickness controllability.
  • a method of spin-coating a silane coupling agent solution is preferably used. This is because excellent adhesion can be stably obtained.
  • the concentration of the silane coupling agent in the solution is preferably 0.01 to 5 v / v%, more preferably 0.05 to 1 v / v%.
  • the solvent for the silane coupling agent solution pure water; alcohols such as methanol, ethanol, and isopropyl alcohol; esters such as ethyl acetate, and the like can be used alone or in combination of two or more. Of these, ethanol, methanol and ethyl acetate diluted with pure water are preferred. This is because the effect of improving the adhesion is particularly remarkable.
  • the drying temperature is not particularly limited, but is usually in the range of room temperature (25 ° C) to 170.
  • the drying time depends on the temperature, but is usually 0.5 to 24 hours. Drying may be performed in air, but may be performed in an inert gas such as nitrogen.
  • a nitrogen blow method in which nitrogen is blown onto a substrate while drying is used.
  • a silane coupling agent is applied to the entire surface of the substrate by the LB film pulling method.
  • a micro-hole pattern having hydrophilic and hydrophobic properties can be formed.
  • the hydrophobic treatment can be performed using a printing technique such as a stamp-ink jet.
  • the stamp method uses PDMS resin.
  • PDMS resin is formed by polymerizing silicone oil to form a resin. Even after resinification, the molecular gap is filled with silicone oil. Therefore, when the PDMS resin is brought into contact with a hydrophilic surface, for example, a glass surface, the contacted part becomes strongly hydrophobic and repels water. Using this to form a recess at the position corresponding to the flow path?
  • the DMS block as a stamp and bringing it into contact with a hydrophilic substrate, a flow path by the above-described hydrophobic treatment can be easily manufactured.
  • FIG. 6 is a diagram showing an example of a separation device employing a liquid switch for a sample inlet.
  • This separation device is a device that moves a sample by utilizing the capillary phenomenon and separates the sample by a separation channel 540 according to the molecular size and the like. There is no need to apply external force such as electric power or pressure, and no driving energy is required.
  • This separation device has a configuration in which a separation channel 540 is provided on a substrate 550.
  • An air hole 560 is provided at one end of the separation channel 540, and a buffer inlet 510 for injecting a buffer is provided at the other end.
  • the separation channel 540 is sealed except for the buffer inlet 510 and the air hole 560.
  • the starting portion of the separation channel 540 is connected to a sample quantification tube 530, and the other end of the sample quantification tube 530 is provided with a sample injection port 520.
  • the sample quantification tube 5350 is provided with a stop valve 535 at a position just before the intersection with the separation channel 5450.
  • the stop valve 5 35 has the same structure as that described in FIG. 3 and the related description.
  • FIG. 7 is an enlarged view of the vicinity of the point where the sample quantification tube 530 and the separation channel 540 intersect.
  • a liquid switch is formed at this location.
  • FIG. 7 is a top view of the liquid switch.
  • FIG. 7 (a) shows the switch closed state
  • FIGS. 7 (b) and (c) show the switch open state.
  • a sample quantification tube 530 is connected to the side surface of the separation channel 540.
  • a blocking unit 110 is provided on the upstream side and the downstream side of a region where the separation channel 540 and the sample quantitative tube 530 intersect.
  • a separation portion 113 is formed adjacent to the damming portion 110.
  • the separation section 113 is filled with silica gel powder for sample separation.
  • the silica gel powder is filled into the separation channel 540 by providing a blocking member on the downstream side, and then flowing a mixture of the silica gel powder, the binder, and water into the separation channel 540. Thereafter, the above structure can be obtained by drying and solidifying the mixture.
  • a diverticulum 131 is provided in the sample quantitative tube 5330 serving as a trigger channel.
  • a water-absorbing gel 1 32 is arranged in the diverticulum 13 1.
  • the water-absorbing gel 1332 is preferably made of a water-absorbing polymer or the like that is insoluble in water.
  • the water-absorbing gel 1332 is configured to expand in volume when it comes into contact with the inflowing liquid, thereby filling the space of the diverticulum 1331.
  • FIG. 8 is a top view of the dam unit 110 of FIG.
  • a plurality of hydrophobic regions 191 are regularly arranged at substantially equal intervals.
  • the surface of the quartz substrate is exposed, and the region is a hydrophilic region 192.
  • the hydrophobicity of the damming portion 110 is appropriately controlled.
  • FIG. 7 (a) the liquid surface tip of the buffer 111 is kept in the hydrophobic area 105, and when the trigger liquid is introduced, the buffer 111 smoothly moves to the downstream side. Become fluid.
  • FIG. 7 (a) shows the liquid switch in a standby state.
  • the buffer 111 introduced into the separation channel 540 is blocked in the blocking section 110.
  • the sample 1 1 2 serving as the trigger liquid is introduced at the desired timing. Then, as shown in FIG. 7 (b), the tip of the liquid surface of the sample 112 moves forward and comes into contact with the damming portion 110. In the state shown in Fig. 7 (a), the buffer 111 remains in the damming portion 110, but when the buffer 111 comes into contact with the sample 112 as shown in Fig. 7 (b), the buffer 1 1 1 starts to move to the right (downstream) in the figure.
  • the water-absorbing gel 1332 expands in volume and covers the diverticulum 1311. As a result, the sample 112 can no longer flow to the downstream side of the diverticulum 13 1. That is, the water-absorbing gel 132 functions as a damming member.
  • FIG. 9 is an example of a microchemical reaction device using a liquid switch.
  • This device is composed of a flow channel formed on a quartz substrate by dry etching, a reservoir for storing a solution to be reacted, and a reaction chamber.
  • the sample and the reagent are mixed according to a preset time schedule, and the reaction proceeds continuously.
  • the protein is trypsinized using this apparatus, and MALD I—TOFMS (Matrix-Assisted Laser Deionization-Time of Flight Mass Spectrometer) is used.
  • MALD I—TOFMS Microx-Assisted Laser Deionization-Time of Flight Mass Spectrometer
  • a channel or the like in the illustrated form is formed on the surface of a quartz substrate.
  • This device does not have an external force applying means such as a pump and an electric field, and the liquid proceeds in the flow channel by capillary force.
  • the sample 602 containing the protein introduced into the solution mixing device 600 0 4 and a flow path 606 are branched and flow, and one is guided to the reservoir 612 and the other is guided to the switch 608.
  • the detailed structure of the switch 608 is the structure shown in FIG. 4, and the main channel 101 in FIG. 4 corresponds to the channel 611 in FIG. 9, and the trigger-one channel 102 in FIG. Correspond to the flow path 606 in FIG. When the inflow of the sample 602 becomes a trigger, the switch 608 is opened.
  • the solution tank 610 stores a trypsin digestion solution, and its liquid level is held at a position higher than the liquid level of a flow channel provided in this apparatus.
  • the switch 608 When the switch 608 is in the "closed” state, the trypsin digestion solution is retained at this position.
  • the flow path is opened, the trypsin digest moves to the downstream side (lower side in the figure) of the flow path 6 11. As a result, the tryptic digest is led to the reservoir 612, where it is mixed with the protein-containing sample 602. This mixed liquid is guided from the reservoir 612 to the chamber 616 via the flow path 614.
  • a chamber 63.0 having an opening is provided at the end of the flow path 606.
  • the chamber 6 16 is formed in a large volume and functions as a time delay element. That is, the mixed solution of the protein-containing sample 6.2 and the trypsin digest solution is continuously supplied to the chamber 616 until the chamber is filled, and when the chamber 616 is filled, the mixed solution is supplied. It overflows and moves downstream. Since the switch 608 remains “open”, the trypsin digestion solution is continuously supplied from the solution tank 610, and the sample 602 is also continuously introduced. As a result, the amount of liquid inside the chamber 6 16 gradually increases, and at a certain time, exceeds the capacity and moves downstream. A predetermined time elapses until the chamber 6 16 is filled, during which the protein-containing sample 62 2 is trypsinized at a temperature of 37 ° C. The pH of the solution treated with trypsin is about 7.6.
  • the overflowed trypsin treatment liquid branches out into the flow paths 6 18 and 6 20 and flows out.
  • the trypsin-treated body guided to the flow path 620 serves as a trigger for the switch 652, so that the switch 608 is opened.
  • a chamber 632 having an opening is provided at the end of the flow path 606.
  • 6 N—HC 1 is stored in the solution tank 6 24, and its liquid level is held at a position higher than the liquid level of the flow path provided in this device.
  • the trypsin treatment is performed on the microchip at the designed evening.
  • the reaction time with the trypsin digestion solution can be controlled by adjusting the volume of the chamber 616.
  • a plurality of switch structures are provided for an apparatus combining a ultrafiltration apparatus and a separation apparatus.
  • sample introduction and flow can be performed automatically. Since a pump for applying an external force and a charge applying means are not required, the entire apparatus can be downsized.
  • FIG. 10 is a schematic configuration diagram of an apparatus according to the present embodiment.
  • This device consists of an ultrafiltration device 702 and a separation device 704.
  • the ultrafiltration device 720 has a first channel 716, a second channel 720, and a switch 712 interposed therebetween as main components.
  • the separating device 704 is a device that separates the sample introduced from the switch 726 by the separating unit 730 and collects them from the collecting unit 732.
  • Blood introduced from the sample inlet 714 moves through the first channel 716, Via Luta 710, we reach the intersection area of Switch 712.
  • the switch 712 is in the “open” state, and the buffer in the buffer tank 706 enters the second flow path 720.
  • the buffer moves from the first channel 716 to the downstream side (right side in the figure) together with the plasma that has passed through the outlet 718, and reaches the switch 726 via the channel 724. I do. Some of the samples move to the discharge section 722.
  • the switch 726 has the same structure as the structure shown in FIG. When the buffer containing plasma arrives, switch 726 is in the "open" state. Then, as described in the description of FIG. 7, a predetermined amount of the buffer containing the plasma is introduced into the separation unit 730. A stop valve 7500 is provided on the upstream side of the switch 726, so that a buffer containing plasma is prevented from flowing in an excessive amount.
  • the developing solution introduced from the buffer tank 728 separates the plasma into a plurality of bands 732 according to the molecular weight. Thereafter, at an appropriate timing, the sample is collected from the collecting section 734, and a component fractionated by molecular weight can be obtained.
  • the components recovered in the recovery section 735 are then used for another analysis after a pretreatment and a drying process.
  • proteins are identified by MALDI—TOFMS or the like.
  • FIG. 11A is a schematic configuration diagram of a switch according to the present embodiment.
  • the channel 901 is filled with a buffer 912.
  • a trigger channel 902 is provided on a side surface of the channel 901, and a pump 910 is provided in the trigger channel 902.
  • the pump 910 includes a water-absorbing region 908, a hydrophobic region 906, and a hydrophilic region 904.
  • a buffer is stored in the hydrophilic region 904.
  • Specific examples of the water absorbing region 908 include the following. (i) Configuration with multiple pillars
  • Air 915 exists in the water absorbing region 908 and the trigger channel 902.
  • the pump 910 is provided with an air hole 9505, and is connected to a flow path 9.03 for introducing a trigger liquid (buffer).
  • the trigger liquid When the trigger liquid is introduced into the pump 910 via the flow path 903 from the standby state shown in Fig. 11 (a), it leaks into the hydrophobic area 906 and is stored in the hydrophilic area 904
  • the buffer is brought into contact with the liquid surface of the hydrophobic region 906.
  • the buffer stored in the hydrophilic region 904 moves to the channel 901 side, and is sucked into the columnar body forming region 908 by capillary force.
  • the air 915 existing in this area is pushed out into the flow path 901.
  • the air 915 plays a role of blocking the flow of the buffer 912 in the flow path 901, and the switch is closed.
  • FIG. 12A shows a schematic structure of the switch according to the present embodiment.
  • a first trigger one flow path 920 and a second trigger flow path 926 are provided in communication with a side wall of a main flow path 924.
  • a hydrophobic region 922 is provided at a position where these flow paths intersect.
  • a hydrophobic region 930 is provided in each channel. These hydrophobic regions have a configuration similar to that shown in FIG. 8, and are regions in which circular hydrophobic regions are periodically formed in a predetermined pattern.
  • a buffer 927 remains upstream of the hydrophobic area 922 (left side on the paper).
  • FIG. 12 (b) shows a state in which the trigger liquid has been introduced into the first trigger channel 920.
  • the knocker 9227 and the trigger liquid come into contact, and these form a continuous phase.
  • Buffer 9 27 flows on the downstream side in the right direction in the figure Buffer 9 27 flows. That is, the switch is opened.
  • the liquid moving in the flow path 1102 is fed back to the switch 1101 on the upstream side via the sub flow path 1100.
  • the present invention relates to a switch having a structure that acts by locking and shuts off the flow path 1102.
  • This feedback type switch can be effectively used as a switch for stopping the flow of liquid when a specific chamber is filled. For example, when the liquid reaches the point where the sample quantification tube 530 and the separation channel 540 cross each other in the apparatus in the apparatus shown in Fig. 6, it is assumed that further liquid intrusion is suppressed. Is possible.
  • Figure 13 (b) shows an example of a mechanism that suppresses changes in flow velocity by such a feedback-type operation.
  • a flow path 111 is provided in a substrate 110.
  • the upper part of the substrate 110 is a flow path.
  • the channel 1 1 1 2 is filled with an inert hydrophobic liquid such as mineral oil.
  • a clock line is provided on a microchip, and the flow of liquid in a flow path on the chip is controlled based on the clock line.
  • ESI-MS electrospray ionization mass spectrometry
  • multiple samples refers to samples obtained by alkylating, enzymatically digesting, and desalting proteins of different types, for example, proteins and peptides contained in spots collected by two-dimensional electrophoresis. .
  • FIG. 14 shows the structure of a chip provided with the switch according to the present embodiment.
  • FIG. 14 (a) is a top view of the chip.
  • a flow path 1203 through which the first processed liquid 1204 passes and a flow path 1203 through which the second processed liquid 1205 passes are formed in parallel.
  • a clock channel 1 201 is provided in a direction orthogonal to these. These have a multilayer flow path structure as shown in FIG. 14 (b).
  • FIG. 14B is a sectional view of the chip. It has a structure in which a main flow path substrate 122 and a clock flow path substrate 120 are laminated.
  • a main flow path 1203 is formed on the surface of the main flow path substrate 1220, and a clock flow path 1201 is formed on the surface of the clock flow path substrate 1210.
  • a control flow path 122 The main flow path 1203 is provided with a switch 127.
  • the flow of the clock fluid introduced into the clock channel 1 201 is controlled by the time delay chamber 1 202, and then passes through the control channel 1 2 1 2 Then you reach Switch 127. Then, the flow path 123 is opened, and the first treated liquid 1224 moves to the downstream side, and is guided to the ESI-MS injector.
  • the clock fluid moves to the downstream side of the clock channel 1221, and after another time delay chamber, reaches the switch 122. Since this switch 122 is a switch of a type in which a flow path is closed when a trigger arrives, a clock fluid serves as a trigger to close the flow path 123. Thereafter, the same applies to the flow path 1203 through which the second treated liquid 1205 passes, and the second treated liquid 1205 moves to the downstream side, and the ESI_MS It is led to the injector.
  • FIG. 15 (a) shows the structure of this switch.
  • a damming portion 110 made of a hydrophobic region is provided in a main flow path 101, and a liquid sample 104 is dammed in this portion.
  • the hydrophilic substrate surface is exposed in portions other than the damming portion 110.
  • the structure of the blocking unit 110 is the same as that shown in FIG.
  • Figure 18 is an example. This figure is a cross-sectional view of the switch in Fig. 15 (a) viewed from the side. is there. A lid 141 is provided in the flow path 101, and a projection 140 is provided in the lid 141 as vibration applying means. When the protrusion 140 is broken, vibration is applied to the flow path 101 and the switch is opened.
  • FIG. 19 and FIG. 20 show another example of a method of starting a switch.
  • FIG. 19 the switch is opened by dropping the sample.
  • a flow path 159 is formed between the substrate 155 and the lid 156.
  • a hydrophobic region 153 is interposed between the water retaining region 152 and the water absorbing region 154.
  • An aqueous solution is stored in the water retaining area 152 and an appropriate pressure is applied. Blocked by hydrophobic area 15 3.
  • a hydrophilic sample 150 such as blood onto the hydrophobic region 153
  • the water retaining region 152 and the water absorbing region 154 continue, and the flow starts from left to right in the figure.
  • FIG. 20 shows an example using a moving member.
  • a hydrophobic region 153 is interposed between the water retaining region 152 and the water absorbing region 154.
  • aqueous solution is stored in the water retention area 152 and is blocked by the hydrophobic area 1553.
  • the surface-hydrophilic magnetic material 160 is initially located in the water retention area 152, but it is straddled over the water retention area 152 and water absorption area 154 by externally operating this with a magnet. When it is moved to the position, the water retention area 152 and the water absorption area 154 continue through the hydrophilic surface of the magnetic material 160, and the flow starts from top to bottom in the figure.
  • the diameter of the magnetic body 160 is set to be equal to or larger than the width of the hydrophobic region 153. This allows the switch to operate satisfactorily.
  • FIG. 16 is a schematic diagram showing the configuration of the mass spectrometer.
  • the dried sample is placed on the sample stage. Then, the dried sample is irradiated with a nitrogen gas laser having a wavelength of 337 nm under vacuum. The dried sample then evaporates with the matrix.
  • the sample stage is an electrode, and when a voltage is applied, the vaporized sample flies in a vacuum and is detected by a detection unit including a reflector detector, a reflector, and a linear detector.
  • FIG. 17 is a block diagram of a mass spectrometry system including the drying device of the present embodiment.
  • This system removes some impurities from sample 1001 Perform the following steps: purification 1002, separation 1000 to remove unnecessary components 1003, pretreatment of the separated sample 1005, and drying of the sample after pretreatment 1006.
  • Means. Some or all of these means can be mounted on one or more microchips 108. By continuously processing the sample on the microchip 108, it is possible to identify even a small amount of component efficiently and reliably by a method with less loss.
  • the damming portion is located at a position close to the trigger channel. Specifically, if the point where the center line of the main flow path and the center line of the trigger flow path intersect is defined as the crossing point, the distance between the intersection and the hydrophobic processing section is 1.5 times or less the width of the trigger flow path. It is preferable that the width be equal to or less than the width of the trigger channel. By doing so, a stable switch operation can be realized.
  • the liquid switch can be realized by a flow path pattern drawn with hydrophobic ink without digging a groove for the flow path.
  • Figure 21 shows the structure of the chip.
  • A is a photograph showing a planar structure
  • (B) is a cross-sectional view thereof.
  • a hydrophilic slide glass 800 (white polished frost slide glass pre-cleaned, Matsunami Glass Co., Ltd., water contact angle is about 7 degrees) is used as a substrate, and an oil-based pen for glass (YYF 1 , Super stubborn marker one, Zebra Corporation, water contact angle is about 70 degrees, or X100 W—SD, Pentel White, Pentel Corporation, water contact angle is about 10 0 °), a flow path pattern 809 including a 5 mm wide main flow path 805 part, a 1 mm width trigger flow path 806 part, and a hydrophobic processing part 808 was drawn. .
  • the flow path was realized by tracing the outer circumference with a pen tip having a width of l mm to 2 mm. Since water is excluded from the hydrophobic region, it flows only between the lines of the flow path pattern 809.
  • the hydrophobic processing section 8 08 that stops the liquid in the main flow path 8 05 This was achieved by drawing a line approximately 80 in width with a pen with a sharpened tip.
  • a double-sided tape 800 (Niitoms Co., Ltd.) with a thickness of about 0.3 mm is applied, and a cover glass with a hydrophobic surface is placed on top of it. 0.17-0.25 style silicone coated 20X20 marauder, Matsunami Glass Co., Ltd., contact angle with water is about 85 degrees).
  • the main flow path 805 and the trigger flow path are formed by the vertical gap 803 with a depth of about 0.3 mm created by this and the horizontal gap sandwiched by the hydrophobic flow path patterns 809. 8 06 is formed.
  • FIG. 22 is a series of photographs showing the switching operation of this chip.
  • Fig. 22 (A) shows the initial state.
  • Figure 22 (B) is a photograph after introducing the black ink 807 (SPS-400 # 1, Platinum Fountain Pen) diluted 10 times from the right end of the main channel.
  • the black ink 807 automatically entered the main flow path 805 due to the capillary effect, stopped at the hydrophobic processing section 808, and maintained that state.
  • 8 10 (tap water) was introduced.
  • Figure 22 (C) is the photograph immediately after.
  • the water 810 rapidly enters the trigger channel 806 due to the capillary effect, and at the next moment its liquid level merges with the liquid level of the black ink 807 stopped at the hydrophobic processing section 808.
  • the macro-sized main flow path 805 with a width of 5 mm can be opened by the narrower trigger flow path 806. It was shown that this can be achieved simply by drawing a border with hydrophobic ink.
  • Example 2 In the present embodiment, the ON operation of the liquid switch was confirmed in a narrower flow path of about 100 / im to about 100. Further, the liquid switch of the present embodiment is a prototype produced by photolithography, which means that a channel system including a large number of liquid switches can be integrated on a chip of several centimeters square.
  • FIG. 23 is a plan view showing the structure of a prototype liquid switch. What looks like a T-shape is a groove dug on the silicon substrate 900 by a method described later.
  • a main flow path 905 extending to the left and right, a trigger single flow path 906 intersecting at right angles, and a hydrophobic processing section 908 is provided on the right side of the main flow path 905 across the intersection.
  • Four types were provided according to the thickness of the channel, the width and location of the hydrophobic treatment section 908, and the direction in which the liquid was introduced into the main channel. Each type is referred to by the alphabetic symbols (A) to (D) attached in Fig. 23.
  • a main flow path of 100 m and a trigger flow path of 50 m are provided, and liquid is introduced from the left side opposite to the hydrophobic part 908 as a control (type ( In B), (C), (D), and (E), the liquid is introduced from the right side with the hydrophobic treatment section 908).
  • Type (B) has a main flow path of 100 m and a trigger flow path of 50 m, and a hydrophobic part 908 with a width of 5 im, which is partially missing, is provided immediately before the intersection. You. The hydrophobic portion 908 cannot be seen because it is transparent, but is shown by a dotted line in the plan view of FIG.
  • Type (C) has a 50 zm main flow path and a 50 m trigger flow path, and has a 5 zm wide hydrophobic part 908 with a partial cut-out just before the intersection.
  • Type (D ) Has a main flow path of 100 m and a trigger flow path of 50 m, and a hydrophobic part 908 having a width of 5 m is provided at a position away from the intersection.
  • a 1 mm square liquid reservoir was etched at the end of each channel at the same time as the channels.
  • Photolithography and channel etching of the channel The entire surface of the clean (110) silicon substrate is thermally oxidized to form a thermal oxide film of 2000 angstroms. Next, a photoresist (S1818, Shi1ey Far East Co., Ltd.) is applied, and a quartz chrome mask on which the flow patterns of the liquid switches of the types (A) to (D) are drawn is used. Exposure and image formation removes the photoresist in the flow path pattern and exposes the oxide film. The exposed oxide film is removed with buffered hydrofluoric acid (16 buffered hydrofluoric acid, Morita Chemical Co., Ltd.) to expose the silicon surface.
  • buffered hydrofluoric acid (16 buffered hydrofluoric acid, Morita Chemical Co., Ltd.
  • the photoresist remaining on the substrate is completely removed by washing with acetone and ethanol, washed with water and dried, and then etched with 25% TMAH heated to 90 ° C for about 20 minutes.
  • TMAH TMAH heated to 90 ° C for about 20 minutes.
  • a silicon substrate was obtained in which the flow path pattern portion was etched by about 20 tm. This was immersed in buffered hydrofluoric acid to remove the remaining thermal oxide film.
  • the main flow channel 905 and the width of the main flow channel 905 are 100 m on the mask, but widen by about 10% to 20% after etching. The same applies to one trigger channel.
  • the surface of the silicon substrate on which the flow path pattern has been etched is hydrophobic, it is immersed in concentrated nitric acid at 90 ° C for 40 minutes to make it hydrophilic. Confirm that the surface of the substrate after washing is hydrophilic, and that the water fills the flow channel by the capillary effect.
  • a thin film photoresist (S185, Ship1ey Far East Co., Ltd.) is directly dropped onto the silicon substrate whose surface has become hydrophilic by the chemical oxidation, and spin-coated.
  • the alignment is performed, and then exposure and development are performed.
  • the hydrophobic processing section 908 exposes the flow channel surface.
  • This substrate is placed in a stainless steel container, and silazane is dropped so as not to cover the substrate. Then, the container is sealed and left for one day.
  • the vaporized silazane forms a hydrophobic silazane film in the hydrophobic treatment section 908 (this film is resistant to acetone-ethanol washing).
  • the thin film photoresist on the substrate was removed with acetone and ethanol, washed with water for at least 10 minutes, and then dried using an air gun. The upper surface of the flow channel was left open without a lid.
  • the substrate fabricated by the above method was placed horizontally on the stage of a metallurgical microscope, and this was mounted on a 5 ⁇ or 10 ⁇ objective lens via a CCD attached to the lens barrel. igital H andy cum, Sony).
  • the liquid to be introduced into the flow path is a colorless solution obtained by diluting a surfactant (NCW-610A, Wako Pure Chemical Industries, Ltd.) with distilled water by a factor of 100, and a black ink ( Two types of dye solutions were prepared by diluting SPS-400 # 1, Platinum Fountain Pen Co., Ltd. 10 times.
  • a dilute surfactant is to avoid the problem that when distilled water is used, the flow rate into the flow channel is extremely slow and the flow channel dries on the way because there is no lid. The reason why the approach speed is slow is probably that the application of the thin film photoresist slightly reduced the hydrophilicity of the substrate surface.
  • Fig. 24 is a series of photographs after introducing a colorless solution into the liquid switch (A) from the left side opposite to the hydrophobic processing part 908 (objective lens ⁇ 10). As shown in (1) to (6) in FIG. 24, the colorless solution automatically entered the main flow path 905 and stopped at the hydrophobic processing section 908 after crossing the intersection. From this result, it can be seen that the hydrophobic processing section 908 has an effect of stopping the solution.
  • Figure 25 shows a series of photographs after the dye solution was introduced into the main flow channel 905 of the type (B) liquid switch from the right side (objective lens ⁇ 10).
  • the main flow stopped at the hydrophobic processing section 908.
  • a part of the dye solution passed through the gap between the hydrophobic processing part 908 and the flow path wall and reached the intersection, but did not proceed any further (Fig. 25 (2)).
  • a colorless liquid was introduced into the trigger channel 906
  • the liquid level merged with the dye liquid level that had stopped earlier (Fig. 25 (3)).
  • the dye solution was passed through the main flow channel 905 on the left side of the intersection beyond the hydrophobic processing portion 908.
  • Figure 26 shows a series of photographs after the dye solution was introduced into the main channel 905 of the type (C) liquid switch from the right side (5x objective lens).
  • the dye solution was stopped at the hydrophobic treatment section 908 (FIG. 26 (1)).
  • Trigger When the colorless liquid is supplied from one channel 906, the colorless liquid merges with the liquid surface stopped at the intersection (Fig. 26 (4)), and the merged liquid surface starts moving again. Then, it proceeded to the left side of the main flow passage 905 beyond the intersection of the main flow passage 905. However, in this case, the colorless liquid supplied from the trigger flow path 906 was not the dye liquid that proceeded in the main flow path 905. From this result, it is understood that the switch operation cannot be performed depending on the relationship between the thickness of the main flow path 905 and the thickness of the trigger single flow path 906 and the amount of the supplied liquid.
  • Figure 27 shows a series of photographs after the dye was introduced into the main flow channel 905 of the type (D) liquid switch from the right side (5x objective lens). After the dye solution automatically entered the main flow path 905, it stopped at the hydrophobic processing section 908 (FIG. 27 (1)). Next, when a colorless liquid was introduced into the trigger channel 906, the colorless liquid was not sufficiently guided to the hydrophobic treatment section 908, and the switch operation was somewhat unstable (Fig. 27 (2)). .
  • the hydrophobic processing section 908 is preferably provided at a location close to the intersection. If the point of intersection of each center line of the main flow path 900 and the trigger flow path 906 is defined as an intersection, the distance between the intersection and the hydrophobic processing section 908 is the width of the trigger flow path 906 The width is preferably 1.5 times or less, and more preferably the width of one trigger channel 906 or less. This makes it possible to realize a stable switch operation.
  • the distance is 100 / m, and the width of the trigger channel 906 is about 50 to 60 m.
  • the ON operation of the liquid switch can be realized even with a flow path as thin as 1 mm or less, and because it can be manufactured by photolithography technology, it can be integrated, and to realize stable ON operation It is preferable to consider the position of the intersection and the hydrophobic processing part 908, and the surface activity of the solution.

Abstract

A liquid sample (104) introduced in a main flow passage (101) is held in a dam portion (105), and a trigger liquid (106) is filled in a trigger flow passage (102). In this state, the trigger liquid (106) is further introduced at desired timing into the trigger flow passage (102) so that the front end portion of the level of the trigger liquid (106) is advanced and the front end portion is brought to be into contact with the dam portion (105). This causes the liquid sample (104) to move to the right (downstream side) in the figure, resulting in the liquid sample (104) flowing out to the downstream side of the main flow passage (101). This means that the trigger liquid (106) provides priming to realize a liquid switch.

Description

明 細 書 液体スィツチおよびそれを用いたマイクロチップ、 質量分析システム 技術分野  Description Liquid switch, microchip and mass spectrometry system using the same
本発明は、液体の流動を制御する液体スィツチおよびそれを用いたマイク 口チップ、 質量分析システムに関するものである。 背景技術  The present invention relates to a liquid switch for controlling the flow of a liquid, a microphone chip using the same, and a mass spectrometry system. Background art
近年、 試料の前処理 ·反応 ·分離 ·検出などの化学操作をマイクロチップ 上で行うマイクロ化学分析 (//一 T A S ) が急速に発展しつつある。 マイク 口化学分析によれば、 使用する試料が微量で済み、 環境負荷も小さく高感度 な分析が可能となる。  In recent years, microchemical analysis (// I T A S), in which chemical operations such as sample pretreatment, reaction, separation, and detection are performed on a microchip, is rapidly developing. According to the microphone mouth chemical analysis, only a small amount of sample is required, and the environmental load is small and highly sensitive analysis is possible.
特許文献 1には、基板上に溝やリザーバを設けた構成のマイクロチャンネ ル型チップにより、 キヤビラリ電気泳動を実現する装置が記載されている。 この種のマイクロチップにおいては、チップ内の流路に試料ゃバッファを導 入するタイミングを精密に制御することが重要となる。 こうした技術は、 分 離装置や分析装置のみならず、マイクロ化学反応装置などにおいても同様に 求められる。  Patent Document 1 describes an apparatus that realizes capillary electrophoresis using a microchannel type chip having a configuration in which a groove and a reservoir are provided on a substrate. In this type of microchip, it is important to precisely control the timing at which the sample / buffer is introduced into the flow path in the chip. Such techniques are required not only in separation devices and analysis devices, but also in microchemical reaction devices.
従来、 試料を導入するタイミングの制御は、 もっぱら電界や圧力等の外力 付与によって行うことが通常であった。 しかしながら、 この方.式では、 チッ プ内の微量試料の挙動を精密に制御することは困難であった。 また、 外力付 与手段を設ける必要性から、 装置全体が大型化するという問題があつた。 特許文献 1 特開 2 0 0 2— 2 0 7 0 3 1号公報 発明の開示  Conventionally, the timing of introducing a sample is usually controlled exclusively by applying an external force such as an electric field or pressure. However, with this method, it was difficult to precisely control the behavior of a small amount of sample in the chip. In addition, the necessity of providing means for applying external force caused a problem that the entire device became large. Patent Document 1 Japanese Patent Application Laid-Open No. 2000-200703 Disclosure of Invention
本発明は、 上記事情に鑑み、 マイクロチップなどの装置において、 試料や バッファ等の液体の流動を精密に制御し、 試料の分離、 分析あるいは反応を 所望の条件で制御性良く行うスィツチ構造を提供することを目的とする。ま た、 本発明の別の目的は、 外部の制御装置の助けなしに、 1回の試料注入を きっかけとして、毛細管力により複数の工程を適切なタイミングで発動可能 とするスィツチ構造を提供することにある。 The present invention has been made in view of the above circumstances, and in a device such as a microchip, the flow of a liquid such as a sample or a buffer is precisely controlled to separate, analyze, or react a sample. It is an object of the present invention to provide a switch structure which can be controlled under desired conditions with good controllability. Another object of the present invention is to provide a switch structure that enables a plurality of processes to be activated at an appropriate timing by capillary force, triggered by one sample injection, without the aid of an external control device. It is in.
本発明によれば、 第一の液体の通る流路と、 前記流路中に設けられた、 前 記第一の液体を堰き止める堰き止め部と、前記堰き止め部の下流側の箇所で 前記流路に連通し、 前記堰き止め部へ第二の液体を導く トリガー流路と、 を 有することを特徴とする液体スィッチが提供される。  According to the present invention, a flow path through which the first liquid passes, a damming portion provided in the flow passage, which dams the first liquid, and a downstream portion of the damming portion, And a trigger flow passage communicating with the flow passage and guiding the second liquid to the damming portion.
本発明の液体スィツチでは、堰き止め部で前記第一の液体が堰き止められ る。 堰き止め部が第一の液体を吸収し保液する構成であってもよいし、 堰き 止め部自体は第一の液体に対して疎液性を示し、その上流側端部で第一の液 体が堰き止められる構成であってもよい。堰き止め部で堰き止められた液体 試料は、第二の液体と接触したとき、堰き止め部を超えて下流側に流出する。 本発明によれば、 外部の制御装置を設けることなく、 第二の液体の導入によ り、 流路の開通を所望のタイミングで制御性良く実行することができる。 本発明において、 堰き止め部は、 第一の液体を保持する部材を含む構成と することができる。 この構成を採用した場合、 流路に第二の液体が導入され ると、上記部材に保持された第一の液体の液面と第二の液体の液面とが接触 する。 すると、 第一の液体が堰き止め部を超えて下流側に流出する。 こうし て流路の開通を所望のタイミングで制御性良く実行することが可能となる。 このような第一の液体を保持する部材としては、前記堰き止め部における流 路単位体積あたりの流路表面積が、流路の他の部分における流路単位体積あ たりの流路表面積よりも大きくなるように構成された構造が挙げられる。毛 細管力が発生し、 保液作用が発現するからである。 こうした構造体の具体例 としては、 複数の粒子、 多孔質体、 離間して配置された複数の突起部を含む 構造等が挙げられる。  In the liquid switch of the present invention, the first liquid is blocked at the blocking section. The blocking unit may be configured to absorb and retain the first liquid, or the blocking unit itself exhibits lyophobicity to the first liquid, and the first liquid is provided at the upstream end thereof. A configuration in which the body is blocked may be used. The liquid sample blocked by the blocking unit flows out downstream of the blocking unit when coming into contact with the second liquid. ADVANTAGE OF THE INVENTION According to this invention, opening of a flow path can be performed with desired controllability at a desired timing by introducing a 2nd liquid, without providing an external control apparatus. In the present invention, the damming portion may be configured to include a member that holds the first liquid. When this configuration is adopted, when the second liquid is introduced into the flow path, the liquid surface of the first liquid and the liquid surface of the second liquid held by the member come into contact with each other. Then, the first liquid flows out downstream of the damming portion. In this way, it is possible to open the flow path at a desired timing with good controllability. As a member holding such a first liquid, the flow passage surface area per unit volume of the flow passage in the damming portion is larger than the flow passage surface area per unit volume of the flow passage in the other part of the flow passage. And a structure configured so that This is because a capillary force is generated and a liquid retention effect is exhibited. Specific examples of such a structure include a plurality of particles, a porous body, a structure including a plurality of spaced apart protrusions, and the like.
本発明において、 堰き止め部は、 第一の液体に対し疎液性を示す領域を含 む構成とすることができる。 疎液性を示す領域は、 第一の液体に対して疎液 性を示す基板を用いその表面を利用して流路を形成する方法、 あるいは、 そ うした化合物により流路表面を処理する方法等により得られる。疎液性の程 度を調整することにより、 開状態へ円滑に移行するとともに、 開状態になつ た後も円滑な流動状態を実現できる。 ここで、 前記流路における前記流路と 前記トリガー流路の交差する箇所よりもの下流側に、前記第一の液体に対し 疎液性を示す領域をさらに含む構成とすることもできる。 こうすることによ り、 トリガー流路から導入された第二の液体がバンド状の形に維持され、 た とえば成分の分離等に好適な試料を提供することが可能となる。 In the present invention, the damming portion may be configured to include a region that is lyophobic to the first liquid. The lyophobic area is lyophobic to the first liquid It can be obtained by a method in which a flow path is formed using a surface of a substrate having a property and utilizing the surface, or a method in which the surface of the flow path is treated with such a compound. By adjusting the degree of lyophobicity, a smooth transition to the open state and a smooth flow state after the open state can be realized. Here, it is possible to further include a region that is lyophobic to the first liquid on the downstream side of the intersection of the trigger channel and the channel in the channel. By doing so, the second liquid introduced from the trigger channel is maintained in a band-like form, and it is possible to provide a sample suitable for separating components, for example.
本発明において、 トリガー流路に弁構造を備え、 所定量の第二の液体が導 入されると前記弁構造が作動し、前記トリガ一流路が閉止するように構成す ることができる。 こうすることによって、 第二の液体を所定量のみ導入する ことができる。 また、 トリガー流路から導入された第二の液体がバンド状の 形に維持され、たとえば成分の分離等に好適な試料を提供することが可能と なる。 特に、 前述した、 流路とトリガー流路の交差点下流側に、 疎液性の領 域を設けた構成と併用することにより、分離操作に適したバンド形状の試料 導入が安定的に実現される。  In the present invention, a valve structure may be provided in the trigger passage, and when a predetermined amount of the second liquid is introduced, the valve structure may be operated to close the one trigger passage. By doing so, it is possible to introduce only a predetermined amount of the second liquid. In addition, the second liquid introduced from the trigger channel is maintained in a band-like form, so that a sample suitable for, for example, separating components can be provided. In particular, by using in combination with the above-mentioned configuration in which the lyophobic area is provided downstream of the intersection of the flow path and the trigger flow path, a band-shaped sample suitable for separation operation can be stably introduced. .
また本発明によれば、 液体の通る流路と、 前記流路中に設けられた、 前記 液体を堰き止める堰き止め部とを有し、 前記堰き止め部は、 前記液体を保持 する部材を含むことを特徴とする液体スィッチが提供される。  Further, according to the present invention, it has a flow path through which a liquid passes, and a damming portion provided in the flow passage to dam the liquid, wherein the damming portion includes a member holding the liquid. A liquid switch is provided.
このスィッチは、 振動を与える、 あるいは堰き止め部に所定の液状物質を 滴下する等によりスィツチ開状態へ切り替えることができる。液体を保持す る部材としては、前記堰き止め部における流路単位体積あたりの流路表面積 が、流路の他の部分における流路単位体積あたりの流路表面積よりも大きく なるように構成された構造が挙げられる。 毛細管力が発生し、 保液作用が発 現するからである。 こうした構造体の具体例としては、 複数の粒子、 多孔質 体、 離間して配置された複数の突起部等が挙げられる。  The switch can be switched to the open state by applying vibration, or by dropping a predetermined liquid substance on the damming portion. The member holding the liquid was configured such that the flow path surface area per unit volume of the flow path in the damming portion was larger than the flow path surface area per unit volume of the flow path in the other part of the flow path. Structure. This is because a capillary force is generated and a liquid retaining action is generated. Specific examples of such a structure include a plurality of particles, a porous body, a plurality of protrusions spaced apart, and the like.
また本発明によれば、 液体の通る流路と、 前記流路中に設けられた、 前記 液体を堰き止める堰き止め部とを有し、 前記堰き止め部は、 前記液体に対し て疎液性の表面を含むことを特徴とする液体スィツチが提供される。 Further, according to the present invention, it has a flow path through which a liquid passes, and a damming portion provided in the flow passage to dam the liquid. And a liquid switch comprising a lyophobic surface.
このスィッチは、 振動を与える、 あるいは堰き止め部に所定の液状物質を 滴下する等によりスィッチ開状態へ切り替えることができる。疎液性を示す 領域は、上記液体に対して疎液性を示す基板を用いその表面を利用して流路 を形成する方法、 あるいは、 そうした化合物により流路表面を処理する方法 等により得られる。 疎液性の程度を調整することにより、 開状態へ円滑に移 行するとともに、 開状態になった後も円滑な流動状態を実現できる。  The switch can be switched to the open state by applying vibration or by dropping a predetermined liquid substance into the damming portion. The lyophobic region can be obtained by a method of forming a flow channel using the surface of a substrate that is lyophobic to the above liquid, or by treating the surface of the flow channel with such a compound. . By adjusting the degree of lyophobicity, a smooth transition to the open state and a smooth flow state after the open state can be realized.
疎液性を示す領域を設ける上記構成を採用した場合において、 流路中に、 堰き止め部から堰き止め部以外の場所まで移動可能に配置された移動部材 をさらに有し、 移動部材は、 第一の液体に対し親液性を示す表面を有し、 流 路外部から移動部材の位置を調整できるようにしてもよい。 この場合、 移動 部材が疎液性を示す領域の外にあるときはスィッチが閉止した状態となる。 移動部材が疎液性を示す領域に位置したとき、移動 材表面に沿う通路が第 一の液体の流路となり、 流路が開通する。 ここで、 外部から前記移動部材の 位置を調整する位置調整手段をさらに備え、移動部材および前記位置調整手 段のうち、 一方が磁石であり他方が磁性体である構成とすることができる。 こうすることによって、 外部から移動部材の位置を調整できる。  In the case where the above configuration in which the region exhibiting the lyophobicity is provided is adopted, the moving member further includes a moving member disposed in the flow path to be movable from the damming portion to a position other than the damming portion. It may have a surface that shows lyophilicity for one liquid, so that the position of the moving member can be adjusted from outside the channel. In this case, when the moving member is outside the region showing the lyophobicity, the switch is in a closed state. When the moving member is located in the region exhibiting the lyophobicity, the passage along the surface of the moving material becomes the first liquid flow path, and the flow path is opened. Here, a position adjusting means for adjusting the position of the moving member from the outside may be further provided, and one of the moving member and the position adjusting means may be a magnet and the other may be a magnetic material. By doing so, the position of the moving member can be adjusted from the outside.
さらに本発明によれば、 第一の液体の通る流路と、 前記流路に連通する副 流路と、 前記副流路に連通する室と、 前記室に連通し、 前記室に第二の液体 を導入するトリガ一流路と、 を備え、 前記室の内部に前記第一の液体に対し て疎液性を示す疎液性物質が貯蔵されており、前記トリガー流路から第二の 液体が導入されたとき、前記室から前記流路へ前記疎液性物質が導入される ように構成されたことを特徴とする液体スィツチが提供される。  Furthermore, according to the present invention, a flow path through which the first liquid passes, a sub flow path communicating with the flow path, a chamber communicating with the sub flow path, a communication path with the chamber, and a second flow path in the chamber A trigger flow path for introducing a liquid; and a lyophobic substance showing lyophobicity with respect to the first liquid is stored inside the chamber, and a second liquid is supplied from the trigger flow path. A liquid switch is provided, wherein the liquid switch is configured to introduce the lyophobic substance from the chamber to the flow path when introduced.
この液体スィッチにおいて、 前記室は、 前記副流路に連通する第一の小室 と、 前記疎液性物質を貯蔵する第二の小室と、 前記第一および第二の小室の 間に介在しこれらの小室を隔てる分離部と、 を備え、 前記トリガ一流路が前 記分離部に連通し、前記トリガー流路から前記室へ第二の液体が導入された とき、前記第一の小室から前記第二の小室へ前記疎液性物質が移動するよう に構成することもできる。 ここで疎液性物質を貯蔵する第二の小室は副流路 と連通しない構造とすることが好ましい。 疎液性物質は、 液体でも気体でも よく、 空気等でもよい。 In this liquid switch, the chamber is interposed between a first chamber communicating with the sub-flow path, a second chamber storing the lyophobic substance, and the first and second chambers. A separation section for separating the small chamber from the first chamber, wherein the trigger one flow path communicates with the separation section and a second liquid is introduced into the chamber from the trigger flow path. So that the lyophobic substance moves to the second compartment Can also be configured. Here, it is preferable that the second small chamber for storing the lyophobic substance has a structure not communicating with the sub flow path. The lyophobic substance may be a liquid or a gas, and may be air or the like.
この液体スィツチは、 トリガ一となる第二の液体の導入を契機として第一 の液体の通る流路に疎液性物質が導入され流路が閉止するように構成され ている。 本発明によれば、 流路中の液体の流動を簡便な構造で確実に閉止す ることができる。  The liquid switch is configured such that a lyophobic substance is introduced into a flow path through which the first liquid flows when the second liquid serving as a trigger is introduced, and the flow path is closed. ADVANTAGE OF THE INVENTION According to this invention, the flow of the liquid in a flow path can be reliably closed with a simple structure.
さらに本発明によれば、 基板と、 該基板上に形成された試料の通る試料流 路と、 該試料流路中に設けられた試料分離部と、 を備え、 前記試料流路中に 上述の液体スィツチが配設されており、前記試料流路から前記試料分離部へ の前記試料の供給が前記液体スィツチにより制御されることを特徴とする マイクロチップが提供される。  Further, according to the present invention, there is provided a substrate, a sample flow path through which a sample formed on the substrate passes, and a sample separation unit provided in the sample flow path, wherein the sample flow path described above is provided in the sample flow path. A microchip is provided, wherein a liquid switch is provided, and the supply of the sample from the sample channel to the sample separation unit is controlled by the liquid switch.
また本発明によれば、 基板と、 該基板上に形成された液体の通る液体流路 と、 該液体流路中に設けられた反応部と、 を備え、 前記液体流路中に上述の 液体スィツチが配設されており、前記液体流路から前記反応部への液体の供 給が前記液体スィッチにより制御されることを特徴とするマイクロチップ が提供される。  According to the present invention, there is provided a substrate, a liquid flow path formed on the substrate, through which a liquid passes, and a reaction unit provided in the liquid flow path. A microchip is provided, wherein a switch is provided, and supply of liquid from the liquid flow path to the reaction section is controlled by the liquid switch.
このマイクロチップにおいて、前記反応部に連通し試薬の導入されるリザ ーバをさらに備え、前記リザーバから前記反応部に至る液体流路に前記液体 スィツチが配設されており、前記リザーバから前記反応部への前記試薬の導 入が前記液体スィツチにより制御される構成とすることができる。 試薬は、 たとえばトリプシン消化液等の酵素消化液とすることができる。  The microchip further includes a reservoir that communicates with the reaction section and into which a reagent is introduced. The liquid switch is disposed in a liquid flow path from the reservoir to the reaction section, and the liquid switch is provided from the reservoir. The introduction of the reagent into the section may be controlled by the liquid switch. The reagent can be, for example, an enzyme digestion solution such as a trypsin digestion solution.
また本発明によれば、基板と、該基板上に形成された液体の通る主流路と、 前記液体が前記主流路の所定箇所に通過する時期を制御するクロック流路 と、 前記主流路とクロック流路とに連通する制御流路と、 を備え、 前記制御 流路に上述の液体スィツチが配設されており、前記主流路における前記液体 の進行が前記液体スィツチにより制御されることを特徵とするマイクロチ ップが提供される。 本発明によれば、 クロック流路の利用により、 チップ上で行う分離操作や 反応等の様々な処理を時間の制御性良く実行することが可能となる。 Further, according to the present invention, a substrate, a main flow path through which a liquid formed on the substrate passes, a clock flow path that controls a timing at which the liquid passes through a predetermined portion of the main flow path, and a main flow path and a clock A control flow path communicating with the flow path, wherein the control flow path is provided with the above-described liquid switch, and the progress of the liquid in the main flow path is controlled by the liquid switch. Microchips are provided. According to the present invention, various processes such as a separation operation and a reaction performed on a chip can be executed with good time controllability by using a clock channel.
これらのマイクロチップは、液体スィツチにより試料の分離や反応を所望 の条件で制御性良く行うことができる。特にクロックラインを設けた構成に よれば、所定のスケジュールにしたがって適切なタイミングで液体の混合や 反応、 分離等を行うことができる。  These microchips can perform sample separation and reaction under desired conditions with good controllability using a liquid switch. In particular, according to the configuration provided with the clock line, liquid mixing, reaction, separation, and the like can be performed at an appropriate timing according to a predetermined schedule.
さらに本発明によれば、生体試料を分子サイズまたは性状に応じて分離す る分離手段と、 前記分離手段により分離された試料に対し、 酵素消化処理を 含む前処理を行う前処理手段と、前処理された試料を乾燥させる乾燥手段と、 乾燥後の試料を質量分析する質量分析手段と、 を備え、 前記分離手段は、 上 述のマイクロチップを含むことを特徴とする質量分析システムが提供され る。  Further, according to the present invention, a separation means for separating a biological sample according to a molecular size or a property, a pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means, A mass spectrometry system is provided, comprising: drying means for drying the processed sample; and mass spectrometry means for mass analyzing the dried sample, wherein the separation means includes the microchip described above. You.
また本発明によれば、生体試料を分子サイズまたは性状に応じて分離する 分離手段と、 前記分離手段により分離された試料に対し、 酵素消化処理を含 む前処理を行う前処理手段と、 前処理された試料を乾燥させる乾燥手段と、 乾燥後の試料を質量分析する質量分析手段と、 を備え、 前記前処理手段は、 上述のマイクロチップを含むことを特徴とする質量分析システムが提供さ れる。  Further, according to the present invention, a separation means for separating a biological sample according to a molecular size or a property, a pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means, A mass spectrometry system comprising: drying means for drying the processed sample; mass spectrometry means for mass analyzing the dried sample; wherein the pretreatment means includes the microchip described above. It is.
また本発明によれば、生体試料を分子サイズまたは性状に応じて分離する 分離手段と、 前記分離手段により分離された試料に対し、 酵素消化処理を含 む前処理を行う前処理手段と、 前処理された試料を乾燥させる乾燥手段と、 乾燥後の試料を質量分析する質量分析手段と、 を備え、 前記分離手段、 前記 前処理手段または前記乾燥手段が、上述のマイクロチップを含むことを特徴 とする質量分析システムが提供される。  Further, according to the present invention, a separation means for separating a biological sample according to a molecular size or a property, a pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means, A drying unit for drying the processed sample; and a mass analysis unit for mass analyzing the dried sample, wherein the separation unit, the pretreatment unit, or the drying unit includes the microchip described above. Is provided.
これらの質量分析システムによれば、質量分析用に適した試料を効率よく 調整できる。  According to these mass spectrometry systems, samples suitable for mass spectrometry can be efficiently adjusted.
以上説明したように本発明によれば、マイクロチップなどの装置において、 試料やバッファ等の液体の流動を精密に制御し、 試料の分離、 分析あるいは 反応を所望の条件で制御性良く行うスィツチ構造が提供される。 図面の簡単な説明 As described above, according to the present invention, in a device such as a microchip, the flow of a liquid such as a sample or a buffer is precisely controlled to separate, analyze, or A switch structure for performing a reaction under desired conditions with good controllability is provided. BRIEF DESCRIPTION OF THE FIGURES
上述した目的、 およびその他の目的、 特徴および利点は、 以下に述べる好適 な実施の形態、およびそれに付随する以下の図面によってさらに明らかにな る。 The above and other objects, features and advantages will become more apparent from the preferred embodiments described below and the accompanying drawings.
図 1は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 1 is a diagram illustrating a switch structure according to an embodiment.
図 2は、実施の形態に係るスィツチ構造に含まれる堰き止め部の構造を示 す図である。  FIG. 2 is a diagram illustrating a structure of a damming portion included in the switch structure according to the embodiment.
図 3は、 実施の形態に係るスィッチ構造における、 トリガー液保持のため の弁構造を示す図である。  FIG. 3 is a diagram showing a valve structure for holding a trigger liquid in the switch structure according to the embodiment.
図 4は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 4 is a diagram illustrating a switch structure according to the embodiment.
図 5は、 実施の形態に係るスィツチの断面構造を示す図である。  FIG. 5 is a diagram showing a cross-sectional structure of the switch according to the embodiment.
図 6は、 実施の形態に係る分離装置の構造を示す図である。  FIG. 6 is a diagram showing a structure of the separation device according to the embodiment.
図 7は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 7 is a diagram showing a switch structure according to the embodiment.
図 8は、実施の形態に係るスィツチ構造に含まれる堰き止め部の構造を示 す図である。  FIG. 8 is a diagram showing a structure of a damming portion included in the switch structure according to the embodiment.
図 9は、 実施の形態に係るマイクロ化学反応装置の構造を示す図である。 図 1 0は、 実施の形態に係る装置の構造を示す図である。  FIG. 9 is a diagram showing the structure of the microchemical reaction device according to the embodiment. FIG. 10 is a diagram showing the structure of the device according to the embodiment.
図 1 1は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 11 is a diagram showing a switch structure according to the embodiment.
図 1 2は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 12 is a diagram showing a switch structure according to the embodiment.
図 1 3は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 13 is a diagram showing a switch structure according to the embodiment.
図 1 4は、 実施の形態に係るチップの構造を示す図である。  FIG. 14 is a diagram showing the structure of the chip according to the embodiment.
図 1 5は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 15 is a diagram showing a switch structure according to the embodiment.
図 1 6は、 質量分析装置の構成を示す概略図である。  FIG. 16 is a schematic diagram showing the configuration of the mass spectrometer.
図 1 7は、 質量分析システムのブロック図である。  Figure 17 is a block diagram of the mass spectrometry system.
図 1 8は、 実施の形態に係るスィッチ構造を示す図である。  FIG. 18 is a diagram showing a switch structure according to the embodiment.
図 1 9は、 実施の形態に係るスィツチ構造を示す図である。 図 2 0は、 実施の形態に係るスィッチ構造を示す図である。 FIG. 19 is a diagram showing a switch structure according to the embodiment. FIG. 20 is a diagram showing a switch structure according to the embodiment.
図 2 1は、 実施例に係るスィッチの構造を示す図である。  FIG. 21 is a diagram illustrating the structure of the switch according to the embodiment.
図 2 2は、 実施例に係るスィツチの動作を説明するための図である, 図 2 3は、 実施例に係るスィッチの構造を示す図である。  FIG. 22 is a diagram for explaining the operation of the switch according to the embodiment. FIG. 23 is a diagram illustrating the structure of the switch according to the embodiment.
図 2 4は、. 実施例に係るスィッチの動作を説明するための図である, 図 2 5は、 実施例に係るスィツチの動作を説明するための図である, 図 2 6は、 実施例に係るスィッチの動作を説明するための図である, 図 2 7は、 実施例に係るスィッチの動作を説明するための図である, 発明を実施するための最良の形態  FIG. 24 is a diagram for explaining the operation of the switch according to the embodiment. FIG. 25 is a diagram for explaining the operation of the switch according to the embodiment. FIG. 26 is a diagram for explaining the operation of the switch according to the embodiment. FIG. 27 is a diagram for explaining the operation of the switch according to the embodiment. FIG. 27 is a diagram for explaining the operation of the switch according to the embodiment.
以下、 本発明の実施の形態について図面を参照して説明する。 各実施の形 態に示すスィツチは、基板上に流路ゃリザーパ等を備えた構成のマイクロチ ップにおいて、 流路を移動する液体の制御に用いられる。  Hereinafter, embodiments of the present invention will be described with reference to the drawings. The switch described in each embodiment is used for controlling a liquid moving in a flow path in a microchip having a flow path and a reservoir on a substrate.
以下の説明では特にことわりがない限り、導入される液体は水溶液とする。 また、 以下の各施形態では基板として石英基板を用いるが、 他の基板材料と して、 プラスチック材料、 シリコン等を用いてもよい。 プラスチック材料と して、 たとえばシリコン樹脂、 P MM A (ポリメタクリル酸メチル)、 P E T (ポリエチレンテレフタレート)、 P C (ポリカーボネート) 等の熱可塑 性樹脂や、 エポキシ樹脂などの熱硬化性樹脂等が挙げられる。 このような材 料は成形加工が容易であり、 製造コストを抑えることができる。 また、 マイ クロチップの流路ゃリザ一バ等の部分を形成する方法としては、 フォトリソ グラフィおよびエッチングを組み合わせた方法が挙げられるが、基板材料と してプラスチック材料を用いた場合は、 射出成形、 ホットェンポシング等の 方法を採用することができる。  In the following description, the liquid to be introduced is an aqueous solution unless otherwise specified. In each of the following embodiments, a quartz substrate is used as a substrate, but a plastic material, silicon, or the like may be used as another substrate material. Examples of the plastic material include thermoplastic resins such as silicone resin, PMMA (polymethyl methacrylate), PET (polyethylene terephthalate), and PC (polycarbonate), and thermosetting resins such as epoxy resin. . Such a material is easy to mold and can reduce the manufacturing cost. In addition, as a method for forming a portion of the microchip such as a flow path and a reservoir, a method combining photolithography and etching can be cited, but when a plastic material is used as a substrate material, injection molding, A method such as hot embossing can be adopted.
また、以下の実施の形態では毛細管力により流路内を液体が進行する装置 を例に挙げて説明するが、 ポンプや電界、 引力等の外力を利用して液体を進 行させる構成とすることもできる。  Also, in the following embodiments, an example will be described in which a liquid advances in a flow path by capillary force.However, a configuration in which a liquid advances using an external force such as a pump, an electric field, or an attractive force will be described. You can also.
第 1の実施の形態 本実施形態では、試料堰き止め部に液体を保持する部材を配置した液体ス イッチの例を示す。 この液体スィッチは、 石英基板表面に溝部を形成するこ とにより作製することができる。 石英基板の表面は親水性であるので、 溝部 内壁は親水性表面となっている。 このスィツチを含む装置はポンプや電界等 の外力印加手段を有さず、 毛細管力により流路内を液体が進行していく。 図 1は、 この液体スィッチの上面図であり、図 1 ( a )はスィッチ閉状態、 図 1 ( b )、 (c ) はスィッチ開状態を示す。 図中、 主流路 1 0 1の側面にト リガ一流路 1 0 2が接続している。 トリガ一流路 1 0 2は、 流路内の親水性 の程度や流路径等を適宜に調整することによって、流路内の液体の進行速度 を調整することができる。 これにより、 スィッチ動作の速度を調整できる。 主流路 1 0 1とトリガー流路 1 0 2の交差する領域の上流側 (図中左側) に 堰き止め部 1 0 5が設けられている。 堰き止め部 1 0 5は、 流路の他の部分 よりも強い毛細管力を有する部分となっている。堰き止め部 1 0 5の具体的 構成としては、 以下のものが例示される。 First embodiment In the present embodiment, an example of a liquid switch in which a member for holding a liquid is arranged in a sample damming portion will be described. This liquid switch can be manufactured by forming a groove on the surface of the quartz substrate. Since the surface of the quartz substrate is hydrophilic, the inner wall of the groove has a hydrophilic surface. The device including this switch has no means for applying an external force such as a pump or an electric field, and the liquid proceeds in the flow channel by the capillary force. FIG. 1 is a top view of the liquid switch. FIG. 1 (a) shows the switch in a closed state, and FIGS. 1 (b) and 1 (c) show the switch in an open state. In the figure, a single trigger channel 102 is connected to a side surface of the main channel 101. In the trigger one flow path 102, the traveling speed of the liquid in the flow path can be adjusted by appropriately adjusting the degree of hydrophilicity in the flow path, the flow path diameter, and the like. Thereby, the speed of the switch operation can be adjusted. A damming portion 105 is provided on the upstream side (left side in the figure) of the area where the main flow path 101 and the trigger flow path 102 intersect. The blocking portion 105 is a portion having a stronger capillary force than other portions of the flow path. The following is an example of a specific configuration of the blocking unit 105.
(i)複数の柱状体が配設された構成  (i) Configuration with multiple pillars
この構成では、堰き止め部 1 0 5における流路単位体積あたりの流路表面 積が、 流路の他の部分のそれよりも大きくなつている。 すなわち、 主流路 1 0 1に液体が満たされたとき、 流路堰き止め部 1 0 5においては、 流路の他 の部分よりも表面積が大きく、固液界面が大きくなるように構成されている。 (i i)多孔質体やビーズが複数充填された構成  In this configuration, the flow channel surface area per unit volume of the flow channel in the damming portion 105 is larger than that of the other portion of the flow channel. That is, when the main flow path 101 is filled with liquid, the flow path damming portion 105 is configured to have a larger surface area and a larger solid-liquid interface than the other parts of the flow path. . (i i) Configuration filled with multiple porous bodies and beads
この構成では、 流路堰き止め部 1 0 5において、 流路の他の部分よりも表 面積が大きく、 固液界面が大きくなるように構成されている。  In this configuration, the surface of the flow passage blocking portion 105 is configured to have a larger surface area and a larger solid-liquid interface than the other portions of the flow passage.
上記(i)の構成とする場合、 柱状体は、 基板の種類に応じて適宜な方法で 形成することができる。 石英基板や石英基板を用いる場合、 フォトリソダラ フィ技術およびドライエッチング技術を利用して形成することができる。プ ラスチック基板を用いる場合、形成しょうとする柱状体のパターンの反転パ ターンを有する金型を作製し、 この金型を用いて成形を行い所望の柱状体パ ターン面を得ることができる。 なお、 このような金型は、 フォトリソグラフ ィ技術およびドライエッチング技術を利用することにより形成することが できる。 In the case of the above configuration (i), the columnar body can be formed by an appropriate method according to the type of the substrate. When a quartz substrate or a quartz substrate is used, it can be formed using a photolithography technique and a dry etching technique. When a plastic substrate is used, a mold having an inverted pattern of the pattern of the pillar to be formed is manufactured, and molding is performed using the mold to obtain a desired pillar pattern surface. In addition, such a mold is used for photolithography. It can be formed by utilizing the etching technology and the dry etching technology.
上記(i i )の構成とする場合、 多孔質体やビーズは、 これらを流路の所定箇 所に直接充填、 接着することにより形成することができる。  In the case of the above configuration (i i), the porous body and beads can be formed by directly filling and adhering them to predetermined locations in the flow channel.
本実施形態では、 上記(i )の構成を採用する。  In the present embodiment, the configuration of the above (i) is adopted.
図 2は、 堰き止め部 1 0 5の上面図である。 複数の柱状体 1 2 1が、 略等 間隔で規則的に配置されている。柱状体 1 2 1以外の領域は微細流路 1 2 2 となっている。堰き止め部 1 0 5では、流路単位体積あたりの流路表面積が、 流路の他の部分のそれよりも大きい。 このため、 堰き止め部 1 0 5に浸入し た液体は、 毛細管力により、 微細流路 1 2 2に保持される。  FIG. 2 is a top view of the blocking unit 105. The plurality of pillars 1 2 1 are regularly arranged at substantially equal intervals. The area other than the columnar body 1 2 1 is a fine channel 1 2 2. In the damming portion 105, the flow channel surface area per unit volume of the flow channel is larger than that of other portions of the flow channel. For this reason, the liquid that has entered the damming portion 105 is retained in the fine channel 122 by capillary force.
図 1 ( a ) はスタンバイ状態にある液体スィッチを示している。 主流路 1 0 1に導入された液体試料 1 0 4が堰き止め部 1 0 5で保持されている。 こ の状態から所望のタイミングでトリガー液 1 0 6が導入されると、図 1 ( b ) のようにトリガー液 1 0 6の液面の先端部分が前進し、堰き止め部 1 0 5と 接触することとなる。 図 1 ( a ) の状態では、 液体試料 1 0 4は毛細管力に より堰き止め部 1 0 5に保持されているが、液体試料 1 0 4がトリガー液 1 0 6と接触した図 1 ( b )の状態になると、液体試料 1 0 4が図中右方向(下 流側) に移動し、 図 1 ( c ) の主流路 1 0 1下流側に液体試料 1 0 4が流出 する。 すなわち、 トリガー液 1 0 6が呼び水としての役割を果たし、 液体ス イッチとしての動作が発現する。  FIG. 1 (a) shows the liquid switch in a standby state. The liquid sample 104 introduced into the main flow path 101 is held by the damming portion 105. When the trigger liquid 106 is introduced at a desired timing from this state, the leading end of the liquid surface of the trigger liquid 106 advances as shown in FIG. 1 (b), and comes into contact with the damming portion 105. Will be done. In the state shown in Fig. 1 (a), the liquid sample 104 is held in the damming portion 105 by capillary force, but the liquid sample 104 comes into contact with the trigger solution 106 in Fig. 1 (b). ), The liquid sample 104 moves to the right (downstream side) in the figure, and the liquid sample 104 flows out to the downstream side of the main flow path 101 in FIG. 1 (c). That is, the trigger liquid 106 plays a role as priming water, and the operation as a liquid switch is developed.
以上説明したスィッチは、スィッチ開状態となったとき主流路 1 0 1へト リガ一液 1 0 6が連続的に供給されることとなる。 しかし、 スィッチを設け る目的によっては、主流路 1 0 1へのトリガ一液 1 0 6の混入を最小限に抑 えることが必要となる場合がある。 このような制御は一般に困難であるが、 例えば図 3に示す弁構造を用いれば、 こうした制御を確実に行うことができ る。 図 3 ( a ) に示す弁構造では、 流路の上流側から下流側に向かって、 液 体試料流入路 1 3 0、憩室 1 3 1および液体試料流出路 1 3 4がこの順で設 けられている。 憩室 1 3 1中には吸水ゲル 1 3 2が配置されている。 吸水ゲ ル 1 3 2は、 流入した液体に接触すると体積が膨張し、 憩室 1 3 1の空間を 埋め尽くすように構成されている。 図 3 ( b ) は憩室 1 3 1にトリガ一液が 導入され、 吸水ゲル 1 3 2が体積膨張した状態を示す図である。 この状態に おいては、液体試料流入路 1 3 0の上流側から導入された流体はもはや憩室 1 3 1の下流側には流出することができない。すなわち吸水ゲル 1 3 2が堰 き止め部材として機能することとなる。 In the switch described above, the trigger liquid 106 is continuously supplied to the main flow passage 101 when the switch is in the open state. However, depending on the purpose of providing the switch, it may be necessary to minimize the mixing of the trigger liquid 106 into the main flow path 101. Although such control is generally difficult, such control can be reliably performed by using, for example, a valve structure shown in FIG. In the valve structure shown in Fig. 3 (a), the liquid sample inflow path 130, the diverticule 131, and the liquid sample outflow path 134 are arranged in this order from the upstream side to the downstream side of the flow path. Have been. In the diverticulum 1 31, a water-absorbing gel 1 3 2 is arranged. Water absorption The volume 13 2 is configured to expand in volume when it comes into contact with the inflowing liquid, and to fill the space of the diverticulum 13 1. FIG. 3 (b) is a diagram showing a state in which the trigger one solution is introduced into the diverticulum 131, and the volume of the water-absorbing gel 132 is expanded. In this state, the fluid introduced from the upstream side of the liquid sample inflow path 130 can no longer flow out of the diverticule 13 1. That is, the water-absorbing gel 132 functions as a damming member.
第 2の実施の形態  Second embodiment
本実施形態は、堰き止め部材として疎水領域を用いたスィツチ構造に関す るものである。 この液体スィッチは、 石英基板表面に溝部を形成することに より作製することができる。石英基板を用いるため溝部内壁は親水性表面と なっている。 疎水領域は、 石英ガラス表面を有するふた部を疎水処理するこ とにより得られる。  The present embodiment relates to a switch structure using a hydrophobic region as a damming member. This liquid switch can be manufactured by forming a groove on the surface of the quartz substrate. Since a quartz substrate is used, the inner wall of the groove has a hydrophilic surface. The hydrophobic region can be obtained by subjecting a lid having a quartz glass surface to a hydrophobic treatment.
このスィツチは、 図 4 ( a ) に示すように、 主流路 1 0 1の側面にトリガ —流路 1 0 2が接続され、 これらの交差領域の上流側主流路 1 0 1中に疎水 領域からなる堰き止め部 1 1 0が設けられている。疎水領域からなる堰き止 め部 1 1 0を除く主流路 1 0 1およびトリガー流路 1 0 2は親水性領域で ある。 親水性領域と疎水性領域の作り分けは、 本実施形態では以下のように 行っている。 すなわち、 主流路 1 0 1の流路全体に対し、 流路上面を覆う被 覆部材を設けた上で、 この被覆部材の試料接触面を、 堰き止め部 1 1 0にお いては疎水性とし、それ以外の領域においては親水性としている。図 4 ( a ) に示した流路の断面図はこの状態を説明する図である。左側の断面図におい ては、 石英ガラスから成る被覆部材がそのまま用いられており、 右側の断面 図ではシラザン処理された被覆部材が、シラザン処理面を内側にして配置さ れている。 このスィッチ構造に対し主流路 1 0 1の上流側 (図中左側) から 液体試料 1 0 4を導入すると、堰き止め部 1 1 0の途中までその液面が進行 する。  As shown in Fig. 4 (a), this switch is connected to the side of the main flow path 101, which is connected to the flow path 102, and the upstream main flow path 101 of the intersection area. A damming section 110 is provided. The main flow channel 101 and the trigger flow channel 102 except the damming portion 110 composed of a hydrophobic region are hydrophilic regions. In the present embodiment, the formation of the hydrophilic region and the formation of the hydrophobic region are performed as follows. That is, after providing a covering member for covering the upper surface of the flow channel with respect to the entire flow channel of the main flow channel 101, the sample contact surface of this coating member is made hydrophobic at the damming portion 110. , And the other regions are hydrophilic. The cross-sectional view of the flow channel shown in FIG. 4 (a) illustrates this state. In the cross section on the left, the covering member made of quartz glass is used as it is, and in the cross section on the right, the covering member subjected to silazane treatment is arranged with the silazane treated surface inside. When the liquid sample 104 is introduced into the switch structure from the upstream side (left side in the figure) of the main flow path 101, the liquid level advances halfway through the damming portion 110.
このような状態で、所望のタイミングでトリガー液 1 0 6をさらに導入す ると、 トリガ一液 1 0 6の液面先端が堰き止め部 1 1 0に浸入し、 液体試料 1 0 4の液面先端と接触する (図 4 ( b ) )。 すると、 今まで堰き止め部 1 1 0によって保持されていた液体試料 1 0 4が図中右側の下流側へ向かう駆 動力により流動を開始することとなる。 このようにして、 トリガー液 1 0 6 の導入による液体試料 1 0 4の流動のスイッチングが実現される。 In such a state, when the trigger liquid 106 is further introduced at a desired timing, the leading end of the liquid surface of the trigger liquid 106 enters the damming portion 110, and the liquid sample It comes into contact with the liquid level tip of 104 (Fig. 4 (b)). Then, the liquid sample 104 held by the dam unit 110 starts to flow by the driving force toward the right downstream side in the figure. In this way, the switching of the flow of the liquid sample 104 by the introduction of the trigger liquid 106 is realized.
この実施形態においては、 図 4 ( b ) において液体試料 1 0 4の液面先端 が疎水領域からなる堰き止め部 1 1 0の領域中に留まるようにするととも に、 トリガ一液 1 0 6が導入されたとき液体試料 1 0 4が円滑に流動するよ うに構成することが重要となる。 これを実現するためには、 堰き止め部 1 1 0の疎水性を適度に制御することが望ましい。 これを実現する方法としては、 例えば堰き止め部 1 1 0の疎水処理をする材料の選択,量の最適化などがあ るが、 この他、 流路の構造を好適に設計することによつても可能である。 図 5は、こうした疎水性制御のための構造の一例である。図 5は、図 4 ( a ) の堰き止め部 1 1 0の断面図である。基板 4 0 1中に複数の微細流路 4 0 2 が設けられ、 その上面が被覆材 4 0 3により被覆されている。 微細流路 4 0 2は親水性表面を有し、被覆材 4 0 3はシラザン処理により疎水性処理面を 有する。 この構造においては、 微細流路 4 0 2が複数設けられているため、 毛細管力により適度な保水性が発揮される一方、流路上面の被覆材 4 0 3に より、 疎水性が付与されている。 この構造においては、 毛細管力による保水 性と流路の疎水性の適度なバランスによって液体保持力が決定されること となる。 さらにこの構造においては、 微細流路 4 0 2の数やその幅の制御に より、 疎水性表面と親水性表面の比率の割合を自由に制御でき、 この結果、 全体としての疎水性を所望の値に制御することが可能となる。 こうした構造 の制御、 表面状態の制御により、 疎水性の程度を適度に行うことができる。 本実施形態における疎水処理は、 分子中に、 基板材料と吸着ないし化学結 合するュニッ卜と、疎水性装飾基を有するュニットとを併せ持つ構造の化合 物を、 基板表面に付着ないし結合させること等により実現される。 こうした 化合物として、 たとえばシランカップリング剤等を用いることができる。 疎水基を有するシランカツプリング剤として好ましいものは、へキサメチ ルジシラザン等のシラザン結合基を有するものや、 3—チオールプロピルト リエトキシシラン等のチオール基を有するものが挙げられる。 In this embodiment, in FIG. 4 (b), the liquid surface tip of the liquid sample 104 is made to stay in the area of the damming portion 110 consisting of a hydrophobic area, and the trigger one liquid 106 is formed. It is important to configure the liquid sample 104 to flow smoothly when introduced. In order to realize this, it is desirable to appropriately control the hydrophobicity of the blocking unit 110. As a method of realizing this, for example, there is a method of selecting a material to be subjected to the hydrophobic treatment of the damming portion 110 and optimizing the amount thereof. In addition, by appropriately designing the structure of the flow path, Is also possible. FIG. 5 shows an example of such a structure for controlling hydrophobicity. FIG. 5 is a cross-sectional view of the dam unit 110 of FIG. 4 (a). A plurality of fine flow paths 402 are provided in the substrate 401, and the upper surface thereof is covered with a coating material 403. The microchannel 402 has a hydrophilic surface, and the coating material 403 has a hydrophobic surface by silazane treatment. In this structure, since a plurality of fine channels 402 are provided, appropriate water retention is exhibited by the capillary force, while hydrophobicity is imparted by the coating material 400 on the upper surface of the channels. I have. In this structure, the liquid holding power is determined by an appropriate balance between the water holding ability by the capillary force and the hydrophobicity of the flow channel. Further, in this structure, the ratio of the ratio of the hydrophobic surface to the hydrophilic surface can be freely controlled by controlling the number and width of the microchannels 402, and as a result, the desired overall hydrophobicity is obtained. It can be controlled to a value. By controlling such a structure and controlling the surface state, the degree of hydrophobicity can be appropriately controlled. Hydrophobic treatment in the present embodiment includes, for example, adhering or bonding a compound having a structure in which a unit that adsorbs or chemically bonds to a substrate material in a molecule and a unit having a hydrophobic decorative group are bonded to the substrate surface. Is realized by: As such a compound, for example, a silane coupling agent or the like can be used. Preferred as the silane coupling agent having a hydrophobic group is hexamethine. Examples include those having a silazane binding group such as rudisilazane, and those having a thiol group such as 3-thiolpropyltriethoxysilane.
カップリング剤液等の塗布方法としては、 スピンコート法、 スプレー法、 ディップ法、 気相法等が用いられる。 スピンコート法とは、 カップリング剤 等、結合層の構成材料を溶解または分散させた液をスピンコ一夕一により塗 布する方法である。 この方法によれば膜厚制御性が良好となる。 また、 スプ レー法とは力ップリング剤液等を基板に向けてスプレー噴霧する方法であ り、 ディップ法とは基板をカップリング剤液等に浸漬する方法である。 これ らの方法によれば、 特殊な装置を必要とせず、 簡便な工程で膜を形成するこ とができる。 また気相法とは、 基板を必要に応じて加熱し、 ここにカツプリ ング剤液等の蒸気を流動させる方法である。 この方法によっても膜厚の薄い 膜を膜厚制御性良く形成することができる。 このうち、 シランカップリング 剤溶液をスピンコートする方法が好ましく用いられる。優れた密着性が安定 的に得られるからである。 この際、 溶液中のシランカップリング剤濃度は、 好ましくは 0 . 0 1〜 5 v/v%、 より好ましくは 0 . 0 5〜 1 v/v%とする。 シランカツプリング剤溶液の溶媒としては、純水;メタノール、エタノール、 ィソプロピルアルコール等のアルコール;酢酸ェチル等のエステル類等を単 独または 2種以上を混合して使用できる。 このうち、 純水で希釈したェタノ —ル、 メタノール、 および酢酸ェチルが好ましい。 密着性の向上効果が特に 顕著となるからである。 カップリング剤液等を塗布した後は、 乾燥を行う。 乾燥温度は特に制限がないが、 通常、 室温 (2 5 °C ) 〜 1 7 0 の範囲で行 う。 乾燥時間は、 温度にもよるが、 通常は 0 . 5〜2 4時間とする。 乾燥は 空気中で行っても良いが、 窒素等の不活性ガス中で乾燥させてもよい。 たと えば、窒素を基板に吹き付けながら乾燥させる窒素ブロー法を用いることも できる。 また、 カップリング剤膜の作製方法として、 " NATURE, vo l . 403, 13, J anuary (2000年)" に記載されているように、 L B膜引き上げ法により基 板全面にシランカツプリング剤からなる膜を形成し、親水性 Z疎水性のマイ ク口パターンを形成することができる。 さらに、 この疎水性処理はスタンプゃィンクジエツトなどの印刷技術を用 いて行うこともできる。 スタンプによる方法では、 PDMS樹脂を用いる。 PDMS 樹脂はシリコーンオイルを重合して樹脂化するが、樹脂化した後も分子間隙 にシリコーンオイルが充填された状態となっている。 そのため、 PDMS 樹脂 を親水性の表面、 例えば、 ガラス表面に接触させると、 接触した部分が強い 疎水性となり水をはじく。 これを利用して、 流路部分に対応する位置に凹部 を形成した?DMS ブロックをスタンプとして、 親水性の基板に接触させるこ とにより、 前記の疎水性処理による流路が簡単に製造できる。 As a method of applying the coupling agent solution or the like, a spin coating method, a spray method, a dipping method, a gas phase method, or the like is used. The spin coating method is a method in which a liquid in which a constituent material of a bonding layer, such as a coupling agent, is dissolved or dispersed, is applied all over a spin core. According to this method, the film thickness controllability is improved. The spray method is a method of spraying a force coupling agent liquid or the like toward a substrate, and the dipping method is a method of dipping the substrate in a coupling agent liquid or the like. According to these methods, a film can be formed by a simple process without requiring a special device. The vapor phase method is a method in which a substrate is heated as necessary, and a vapor such as a cutting agent liquid is caused to flow through the substrate. Even with this method, a thin film can be formed with good film thickness controllability. Among them, a method of spin-coating a silane coupling agent solution is preferably used. This is because excellent adhesion can be stably obtained. At this time, the concentration of the silane coupling agent in the solution is preferably 0.01 to 5 v / v%, more preferably 0.05 to 1 v / v%. As the solvent for the silane coupling agent solution, pure water; alcohols such as methanol, ethanol, and isopropyl alcohol; esters such as ethyl acetate, and the like can be used alone or in combination of two or more. Of these, ethanol, methanol and ethyl acetate diluted with pure water are preferred. This is because the effect of improving the adhesion is particularly remarkable. After applying the coupling agent solution, etc., dry. The drying temperature is not particularly limited, but is usually in the range of room temperature (25 ° C) to 170. The drying time depends on the temperature, but is usually 0.5 to 24 hours. Drying may be performed in air, but may be performed in an inert gas such as nitrogen. For example, a nitrogen blow method in which nitrogen is blown onto a substrate while drying is used. As described in “NATURE, vol. 403, 13, January (2000)”, a silane coupling agent is applied to the entire surface of the substrate by the LB film pulling method. And a micro-hole pattern having hydrophilic and hydrophobic properties can be formed. Further, the hydrophobic treatment can be performed using a printing technique such as a stamp-ink jet. The stamp method uses PDMS resin. PDMS resin is formed by polymerizing silicone oil to form a resin. Even after resinification, the molecular gap is filled with silicone oil. Therefore, when the PDMS resin is brought into contact with a hydrophilic surface, for example, a glass surface, the contacted part becomes strongly hydrophobic and repels water. Using this to form a recess at the position corresponding to the flow path? By using the DMS block as a stamp and bringing it into contact with a hydrophilic substrate, a flow path by the above-described hydrophobic treatment can be easily manufactured.
インクジェットプリントによる方法では、粘稠性が低いタイプのシリコ一 ンオイルをィンクジエツトプリントのインクとして用い、流路壁部分にシリ コーンオイルが付着するようなパターンに印刷することによつても同じ効 果が得られる。  In the ink-jet printing method, the same applies to the use of low-viscosity silicone oil as ink for ink jet printing, and printing in a pattern in which the silicone oil adheres to the flow path wall. The effect is obtained.
第 3の実施の形態  Third embodiment
図 6は、試料導入口に液体スィツチを採用した分離装置の例を示す図であ る。 この分離装置は、 毛細管現象を利用して試料を移動させ、 分離用流路 5 4 0により分子サイズ等に応じて試料の分離を行う装置である。 電力、 圧力 等の外力の印加が不要で駆動のためのエネルギーが不要となる。 この分離装 置は、 基板 5 5 0上に分離用流路 5 4 0が設けられた構成を有する。 分離用 流路 5 4 0の一端には空気穴 5 6 0が設けられ、他端にはバッファ一を注入 するためのバッファー注入口 5 1 0が設けられている。分離用流路 5 4 0は、 バッファー注入口 5 1 0、 空気穴 5 6 0の箇所を除き密閉されている。 分離 用流路 5 4 0の起始部には、 サンプル定量管 5 3 0がつながっており、 サン プル定量管 5 3 0の他方の端は、 サンプル注入口 5 2 0が設けられている。 サンプル定量管 5 3 0には、分離用流路 5 4 0と交差する手前の部分に停止 弁 5 3 5が設けられている。 停止弁 5 3 5は、 図 3および関連記載により説 明した構造と同様である。  FIG. 6 is a diagram showing an example of a separation device employing a liquid switch for a sample inlet. This separation device is a device that moves a sample by utilizing the capillary phenomenon and separates the sample by a separation channel 540 according to the molecular size and the like. There is no need to apply external force such as electric power or pressure, and no driving energy is required. This separation device has a configuration in which a separation channel 540 is provided on a substrate 550. An air hole 560 is provided at one end of the separation channel 540, and a buffer inlet 510 for injecting a buffer is provided at the other end. The separation channel 540 is sealed except for the buffer inlet 510 and the air hole 560. The starting portion of the separation channel 540 is connected to a sample quantification tube 530, and the other end of the sample quantification tube 530 is provided with a sample injection port 520. The sample quantification tube 5350 is provided with a stop valve 535 at a position just before the intersection with the separation channel 5450. The stop valve 5 35 has the same structure as that described in FIG. 3 and the related description.
この装置を使用するにあたっては、使用前にバッファー注入口 5 1 0を介 して分離用流路 5 4 0にバッファ一を導入しておく。 図 7は、サンプル定量管 5 3 0と分離用流路 5 4 0とが交差する点の近傍 を拡大して示したものである。 この箇所には液体スィツチが形成されている。 図 7はこの液体スィッチの上面図であり、 図 7 ( a ) はスィッチ閉状態、 図 7 ( b )、 (c ) はスィッチ開状態を示す。 図中、 分離用流路 5 4 0の側面に サンプル定量管 5 3 0が接続している。分離用流路 5 4 0とサンプル定量管 5 3 0の交差する領域の上流側および下流側に堰き止め部 1 1 0が設けら れている。 この交差領域の下流側には、 堰き止め部 1 1 0と隣接して分離部 1 1 3が形成されている。分離部 1 1 3には試料分離用のシリカゲル粉体が 充填されている。 分離用流路 5 4 0へのシリカゲル粉体の充填は、 下流側に 堰き止め部材を設けた上で、 シリカゲル粉体、 バインダ、 および水の混合体 を分離用流路 5 4 0に流し込み、 その後、 この混合体を乾燥、 固化させるこ とにより、 上記構造を得ることができる。 When using this apparatus, the buffer is introduced into the separation channel 540 via the buffer inlet 510 before use. FIG. 7 is an enlarged view of the vicinity of the point where the sample quantification tube 530 and the separation channel 540 intersect. A liquid switch is formed at this location. FIG. 7 is a top view of the liquid switch. FIG. 7 (a) shows the switch closed state, and FIGS. 7 (b) and (c) show the switch open state. In the figure, a sample quantification tube 530 is connected to the side surface of the separation channel 540. A blocking unit 110 is provided on the upstream side and the downstream side of a region where the separation channel 540 and the sample quantitative tube 530 intersect. On the downstream side of the intersection area, a separation portion 113 is formed adjacent to the damming portion 110. The separation section 113 is filled with silica gel powder for sample separation. The silica gel powder is filled into the separation channel 540 by providing a blocking member on the downstream side, and then flowing a mixture of the silica gel powder, the binder, and water into the separation channel 540. Thereafter, the above structure can be obtained by drying and solidifying the mixture.
トリガー流路となるサンプル定量管 5 3 0には、憩室 1 3 1が設けられて いる。 憩室 1 3 1中には、'吸水ゲル 1 3 2が配置されている。 吸水ゲル 1 3 2は、 水に不溶の吸水性ポリマ一等が好ましく用いられ、 流入した液体に接 触すると体積が膨張し、憩室 1 3 1の空間を埋め尽くすように構成されてい る。  A diverticulum 131 is provided in the sample quantitative tube 5330 serving as a trigger channel. In the diverticulum 13 1, a water-absorbing gel 1 32 is arranged. The water-absorbing gel 1332 is preferably made of a water-absorbing polymer or the like that is insoluble in water. The water-absorbing gel 1332 is configured to expand in volume when it comes into contact with the inflowing liquid, thereby filling the space of the diverticulum 1331.
図 8は、 図 7の堰き止め部 1 1 0の上面図である。 複数の疎水領域 1 9 1 が、 略等間隔で規則的に配置されている。 疎水領域 1 9 1以外の領域は石英 基板表面が露出しており親水領域 1 9 2となっている。 このような疎水 Z親 水パターンを形成することにより、堰き止め部 1 1 0の疎水性が適度に制御 される。 この結果、 図 7 ( a ) においてバッファ 1 1 1の液面先端が疎水領 域 1 0 5中に留まるようにするとともに、 トリガー液が導入されたときバッ ファ 1 1 1が円滑に下流側へ流動するようになる。  FIG. 8 is a top view of the dam unit 110 of FIG. A plurality of hydrophobic regions 191 are regularly arranged at substantially equal intervals. In regions other than the hydrophobic region 191, the surface of the quartz substrate is exposed, and the region is a hydrophilic region 192. By forming such a hydrophobic Z lyophilic pattern, the hydrophobicity of the damming portion 110 is appropriately controlled. As a result, in FIG. 7 (a), the liquid surface tip of the buffer 111 is kept in the hydrophobic area 105, and when the trigger liquid is introduced, the buffer 111 smoothly moves to the downstream side. Become fluid.
図 7に戻り、 図 7 ( a ) はスタンバイ状態にある液体スィッチを示してい る。分離用流路 5 4 0に導入されたバッファ 1 1 1が堰き止め部 1 1 0中で 堰き止められている。  Returning to FIG. 7, FIG. 7 (a) shows the liquid switch in a standby state. The buffer 111 introduced into the separation channel 540 is blocked in the blocking section 110.
この状態から、所望のタイミングでトリガー液となる試料 1 1 2が導入さ れると、 図 7 (b) のように試料 1 1 2の液面の先端部分が前進し、 堰き止 め部 1 1 0と接触することとなる。 図 7 (a) の状態では、 バッファ 1 1 1 は堰き止め部 1 1 0中にとどまっているが、バッファ 1 1 1が試料 1 1 2と 接触した図 7 (b) の状態になると、 バッファ 1 1 1が図中右方向 (下流側) へ移動し始める。 From this state, the sample 1 1 2 serving as the trigger liquid is introduced at the desired timing. Then, as shown in FIG. 7 (b), the tip of the liquid surface of the sample 112 moves forward and comes into contact with the damming portion 110. In the state shown in Fig. 7 (a), the buffer 111 remains in the damming portion 110, but when the buffer 111 comes into contact with the sample 112 as shown in Fig. 7 (b), the buffer 1 1 1 starts to move to the right (downstream) in the figure.
ここで、 トリガー流路となるサンプル定量管 5 3 0に試料 1 1 2が導入さ れると、吸水ゲル 1 3 2が体積膨張し、憩室 1 3 1を覆い尽くすようになる。 これにより、試料 1 1 2はもはや憩室 1 3 1の下流側には流出することがで きない状態となる。すなわち吸水ゲル 1 3 2が堰き止め部材として機能する こととなる。  Here, when the sample 112 is introduced into the sample quantitative tube 5330 serving as the trigger channel, the water-absorbing gel 1332 expands in volume and covers the diverticulum 1311. As a result, the sample 112 can no longer flow to the downstream side of the diverticulum 13 1. That is, the water-absorbing gel 132 functions as a damming member.
この作用により、 所定量の試料 1 1 2が分離用流路 540へ導入され、 つ づいて図 7 (c) に示すように、 試料 1 1 2が分離部 1 1 3に導かれ、 試料 中の成分の分離操作が行われる。  By this action, a predetermined amount of the sample 112 is introduced into the separation channel 540, and then the sample 112 is guided to the separation part 113 as shown in FIG. Is carried out.
以上のようにして、 図 6に示す分離装置に試料が円滑に導入される。  As described above, the sample is smoothly introduced into the separation device shown in FIG.
第 4の実施の形態  Fourth embodiment
図 9は、 液体スィッチを用いたマイクロ化学反応装置の一例である。 この 装置は石英基板上にドライエッチングにより形成された流路溝、反応させる 溶液を貯蔵するリザーバおよび反応室により構成されている。 この装置では、 あらかじめ設定されたタイムスケジュールで試料と試薬が混合され、反応が 連続的に進行するように構成されている。 以下、 この装置を用いてタンパク 質をトリプシン処理し、 MALD I— TOFMS (Matrix-Assisted Laser Desorpt ion lonizat ion-Time of Fl ight Mass Spectrometer:マ卜リックス 支援レーザー脱離イオン化飛行時間型質量分析装置)用の試料を調製する例 について説明する。  FIG. 9 is an example of a microchemical reaction device using a liquid switch. This device is composed of a flow channel formed on a quartz substrate by dry etching, a reservoir for storing a solution to be reacted, and a reaction chamber. In this apparatus, the sample and the reagent are mixed according to a preset time schedule, and the reaction proceeds continuously. Hereinafter, the protein is trypsinized using this apparatus, and MALD I—TOFMS (Matrix-Assisted Laser Deionization-Time of Flight Mass Spectrometer) is used. An example of preparing a sample for use is described.
この装置では、石英基板表面に、図示した形態の流路等が形成されている。 この装置はポンプや電界等の外力印加手段を有さず、毛細管力により流路内 を液体が進行していく。  In this apparatus, a channel or the like in the illustrated form is formed on the surface of a quartz substrate. This device does not have an external force applying means such as a pump and an electric field, and the liquid proceeds in the flow channel by capillary force.
溶液混合装置 60 0に導入されたタンパク質を含む試料 6 02は、流路 6 0 4および流路 6 0 6に分岐して流動し、 一方はリザーバ 6 1 2へ導かれ、 他方はスィッチ 6 0 8へ導かれる。スィッチ 6 0 8の詳細構造は図 4に示し た構造となっており、図 4における主流路 1 0 1が図 9の流路 6 1 1に相当 し、 図 4における卜リガ一流路 1 0 2が図 9の流路 6 0 6に相当する。 試料 6 0 2の流入がトリガ一となって、 スィッチ 6 0 8が 「開」 となる。 The sample 602 containing the protein introduced into the solution mixing device 600 0 4 and a flow path 606 are branched and flow, and one is guided to the reservoir 612 and the other is guided to the switch 608. The detailed structure of the switch 608 is the structure shown in FIG. 4, and the main channel 101 in FIG. 4 corresponds to the channel 611 in FIG. 9, and the trigger-one channel 102 in FIG. Correspond to the flow path 606 in FIG. When the inflow of the sample 602 becomes a trigger, the switch 608 is opened.
溶液タンク 6 1 0にはトリプシン消化液が貯蔵されており、 その液面は、 この装置に設けられた流路の液面よりも高い位置に保持されている。スィッ チ 6 0 8が 「閉」 の状態にあるときは、 この部分でトリプシン消化液が留ま るようになっている。 流路が 「開」 となると、 このトリプシン消化液が流路 6 1 1の下流側 (図中下側) へ移動する。 この結果、 トリプシン消化液がリ ザーバ 6 1 2に導かれ、 タンパク質を含む試料 6 0 2と混合する。 この混合 液体は、 リザーバ 6 1 2から流路 6 1 4を経由して室 6 1 6に導かれる。 な お、 流路 6 0 6の先には開口部を備える室 6 3 .0が設けられている。  The solution tank 610 stores a trypsin digestion solution, and its liquid level is held at a position higher than the liquid level of a flow channel provided in this apparatus. When the switch 608 is in the "closed" state, the trypsin digestion solution is retained at this position. When the flow path is opened, the trypsin digest moves to the downstream side (lower side in the figure) of the flow path 6 11. As a result, the tryptic digest is led to the reservoir 612, where it is mixed with the protein-containing sample 602. This mixed liquid is guided from the reservoir 612 to the chamber 616 via the flow path 614. A chamber 63.0 having an opening is provided at the end of the flow path 606.
室 6 1 6は、 大容積に形成されており、 時間遅れ要素として機能する。 す なわち、室 6 1 6には室内が充填されるまでタンパク質を含む試料 6 0 2お よびトリプシン消化液の混合液が供給され続け、 室 6 1 6が充填されると、 この混合液が溢れ出て下流側へ移動するようになっている。スィツチ 6 0 8 は 「開」 となったままであるので、 溶液タンク 6 1 0からトリプシン消化液 が連続的に供給され、 これとともに試料 6 0 2も引き続き連続導入されるこ ととなる。 この結果、 室 6 1 6内部の液体量が次第に増加していき、 ある時 刻においてその収容量を超過して下流側に移動するのである。室 6 1 6が満 たされるまで所定の時間が経過するが、 この間にタンパク質を含む試料 6 0 2が 3 7 °Cの温度下でトリプシン処理される。 なお、 トリプシン処理された 液の p Hは 7 . 6程度である。  The chamber 6 16 is formed in a large volume and functions as a time delay element. That is, the mixed solution of the protein-containing sample 6.2 and the trypsin digest solution is continuously supplied to the chamber 616 until the chamber is filled, and when the chamber 616 is filled, the mixed solution is supplied. It overflows and moves downstream. Since the switch 608 remains “open”, the trypsin digestion solution is continuously supplied from the solution tank 610, and the sample 602 is also continuously introduced. As a result, the amount of liquid inside the chamber 6 16 gradually increases, and at a certain time, exceeds the capacity and moves downstream. A predetermined time elapses until the chamber 6 16 is filled, during which the protein-containing sample 62 2 is trypsinized at a temperature of 37 ° C. The pH of the solution treated with trypsin is about 7.6.
溢れたトリプシン処理液は、流路 6 1 8および流路 6 2 0に分岐して流出 する。 流路 6 2 0に導かれたトリプシン処理体は、 スィッチ 6 5 2のトリガ 一となつて、 スィッチ 6 0 8を 「開」 とする。 なお、 流路 6 0 6の先には開 口部を備える室 6 3 2が設けられている。 溶液タンク 6 2 4には 6 N— H C 1が貯蔵されており、 その液面は、 この 装置に設けられた流路の液面よりも高い位置に保持されている。スィッチ 6The overflowed trypsin treatment liquid branches out into the flow paths 6 18 and 6 20 and flows out. The trypsin-treated body guided to the flow path 620 serves as a trigger for the switch 652, so that the switch 608 is opened. A chamber 632 having an opening is provided at the end of the flow path 606. 6 N—HC 1 is stored in the solution tank 6 24, and its liquid level is held at a position higher than the liquid level of the flow path provided in this device. Switch 6
5 2が 「閉」 の状態にあるときは、 この部分で 6 N— H C 1が留'まるように なっている。 流路が「開」 となると、 この 6 N— H C 1が下流側 (図中下側) へ移動する。 この結果、 6 N— H C 1がリザ一バ 6 2 6に導かれ、 トリプシ ン処理液と混合する。 これにより、 p Hが下がってトリプシン処理の反応が 停止する。 なお p Hを下げる目的は、 反応停止だけでなく、 M A L D I— T O F M Sで用いるマトリクスと混合して測定用試料を調製するのに好適な 状態とする目的もある。 When 5 2 is in the “closed” state, 6 N—H C 1 stays at this point. When the flow path becomes “open”, the 6 N—H C 1 moves downstream (downward in the figure). As a result, 6N—HCl is guided to the reservoir 626, and is mixed with the trypsin-treated solution. This lowers the pH and stops the trypsinization reaction. The purpose of lowering the pH is not only to stop the reaction but also to prepare a sample suitable for measurement by mixing with the matrix used in MALDI-TOFMS.
以上により、 マイクロチップ上で、 トリプシン処理が予め設計した夕イミ ングで実行される。 トリプシン消化液による反応時間は、 室 6 1 6の容積の 調整等により制御可能である。  As described above, the trypsin treatment is performed on the microchip at the designed evening. The reaction time with the trypsin digestion solution can be controlled by adjusting the volume of the chamber 616.
本実施形態においては、 リザ一バ 6 1 2 , 6 2 6に試料 6 0 2が導入され る夕イミングと、 トリプシン消化液や停止液が導入される夕イミングとの調 節が重要となる。本実施形態では、これらのリザーバゃ、溶液タンク 6 1 0、 In the present embodiment, it is important to adjust the timing at which the sample 62 is introduced into the reservoirs 6 12 and 6 26 and the timing at which the trypsin digestion solution and the stop solution are introduced. In the present embodiment, these reservoirs, solution tanks 6 10,
6 2 4の設計、 流路 6 1 1等の設計によって適宜調整することができる。 第 5の実施の形態 It can be adjusted as appropriate by the design of 624 and the design of the flow path 611. Fifth embodiment
本実施形態は、 限界ろ過装置および分離装置を組み合わせた装置に対し、 複数のスィッチ構造を設けたものである。 スィッチ構造の採用により、 試料 の導入、 流動を自動的に行うことができる。 外力を付与するポンプや電荷印 加手段も不要となるため、 装置全体を小型化することができる。  In the present embodiment, a plurality of switch structures are provided for an apparatus combining a ultrafiltration apparatus and a separation apparatus. By adopting a switch structure, sample introduction and flow can be performed automatically. Since a pump for applying an external force and a charge applying means are not required, the entire apparatus can be downsized.
図 1 0は、 本実施形態にかかる装置の概略構成図である。 この装置は、 限 外ろ過装置 7 0 2および分離装置 7 0 4から成る。 限外ろ過装置 7 0 2は、 第 1の流路 7 1 6、第 2の流路 7 2 0およびこれらの間に介在するスィッチ 7 1 2を主要構成部とする。 分離装置 7 0 4は、 スィツチ 7 2 6より導入さ れた試料を分離部 7 3 0により分離し、 これらを回収部 7 3 4から回収する 装置である。 以下、 血液を試料と て分離操作を行う例について説明する。 試料投入口 7 1 4から導入された血液は第一の流路 7 1 6を移動し、 フィ ルタ 7 1 0を経由して、 スィツチ 7 1 2の交差領域まで到達する。 'これによ りスィッチ 7 1 2が 「開」 状態となり、 ノ ッファタンク 7 0 6内のバッファ が第二の流路 7 2 0へ進入する。バッファは第一の流路 7 1 6から排出部 7 1 8を通過した血しょうとともに下流側 (図中右側) に移動していき、 流路 7 2 4を経由してスィッチ 7 2 6へ到達する。 なお、 一部の試料は排出部 7 2 2へ移動する。 FIG. 10 is a schematic configuration diagram of an apparatus according to the present embodiment. This device consists of an ultrafiltration device 702 and a separation device 704. The ultrafiltration device 720 has a first channel 716, a second channel 720, and a switch 712 interposed therebetween as main components. The separating device 704 is a device that separates the sample introduced from the switch 726 by the separating unit 730 and collects them from the collecting unit 732. Hereinafter, an example of performing a separation operation using blood as a sample will be described. Blood introduced from the sample inlet 714 moves through the first channel 716, Via Luta 710, we reach the intersection area of Switch 712. 'Thus, the switch 712 is in the “open” state, and the buffer in the buffer tank 706 enters the second flow path 720. The buffer moves from the first channel 716 to the downstream side (right side in the figure) together with the plasma that has passed through the outlet 718, and reaches the switch 726 via the channel 724. I do. Some of the samples move to the discharge section 722.
スィッチ 7 2 6は、 図 7に示した構造と同様の構造を有する。 血しょうを 含むバッファの到達によりスィッチ 7 2 6は 「開」 状態となる。 すると、 図 7の説明で既に述べたように、 血しょうを含むバッファが所定量、 分離部 7 3 0に導入される。スィツチ 7 2 6の上流側には停止弁 7 5 0が設けられて おり、血しょうを含むバッファが過剰量流入することが抑制される構造とな つている。  The switch 726 has the same structure as the structure shown in FIG. When the buffer containing plasma arrives, switch 726 is in the "open" state. Then, as described in the description of FIG. 7, a predetermined amount of the buffer containing the plasma is introduced into the separation unit 730. A stop valve 7500 is provided on the upstream side of the switch 726, so that a buffer containing plasma is prevented from flowing in an excessive amount.
血しょうを含むバッファが分離部 7 3 0に導入されると、バッファタンク 7 2 8から導入される展開液により、血しょうがその分子量に応じて複数の バンド 7 3 2に分離される。その後適切なタイミングで回収部 7 3 4から試 料を回収し、 分子量により分画された成分を得ることができる。  When the buffer containing plasma is introduced into the separation unit 730, the developing solution introduced from the buffer tank 728 separates the plasma into a plurality of bands 732 according to the molecular weight. Thereafter, at an appropriate timing, the sample is collected from the collecting section 734, and a component fractionated by molecular weight can be obtained.
回収部 7 3 4で回収された成分は、 その後、 前処理、 乾燥工程を経て、 別 の分析に利用される。たとえば M A L D I — T O F M S等によるタンパク質 の同定が行われる。  The components recovered in the recovery section 735 are then used for another analysis after a pretreatment and a drying process. For example, proteins are identified by MALDI—TOFMS or the like.
第 6の実施の形態  Sixth embodiment
本実施形態は、 トリガ一液が到達すると流路が閉止するタイプのスィツチ に関するものである。 図 1 1 ( a ) は本実施形態に係るスィッチの概略構成 図である。 流路 9 0 1中にはバッファ 9 1 2が満たされている。 流路 9 0 1 の側面には、 トリガー流路 9 0 2が設けられ、 トリガー流路 9 0 2にはボン プ 9 1 0が配設されている。  The present embodiment relates to a switch of a type in which a flow path is closed when one liquid of a trigger arrives. FIG. 11A is a schematic configuration diagram of a switch according to the present embodiment. The channel 901 is filled with a buffer 912. A trigger channel 902 is provided on a side surface of the channel 901, and a pump 910 is provided in the trigger channel 902.
ポンプ 9 1 0は、 吸水性領域 9 0 8、 疎水性領域 9 0 6および親水性領域 9 0 4からなる。 親水性領域 9 0 4にはバッファが貯蔵されている。 吸水性 領域 9 0 8の具体的構成としては、 以下のものが例示される。 ( i )複数の柱状体が配設された構成 The pump 910 includes a water-absorbing region 908, a hydrophobic region 906, and a hydrophilic region 904. A buffer is stored in the hydrophilic region 904. Specific examples of the water absorbing region 908 include the following. (i) Configuration with multiple pillars
( i i)多孔質体やビーズが複数充填された構成  (ii) Configuration filled with multiple porous bodies and beads
ここでは(i )の構成を採用する。 Here, the configuration of (i) is adopted.
吸水性領域 9 0 8およびトリガー流路 9 0 2には空気 9 1 5が存在して いる。 ポンプ 9 1 0には空気穴 9 0 5が設けられており、 また、 トリガー液 (バッファ) の導入される流路 9 .0 3が接続されている。  Air 915 exists in the water absorbing region 908 and the trigger channel 902. The pump 910 is provided with an air hole 9505, and is connected to a flow path 9.03 for introducing a trigger liquid (buffer).
図 1 1 ( a ) のスタンバイ状態から、 流路 9 0 3を介してポンプ 9 1 0に トリガー液が導入されると、 疎水性領域 9 0 6に浸みだし、 親水性領域 9 0 4に貯蔵されたバッファが疎水性領域 9 0 6の液面と接触する。 すると、 親 水性領域 9 0 4に貯蔵されたバッファは流路 9 0 1側に移動し、毛細管力に より柱状体形成領域 9 0 8に吸い込まれていく。 すると、 この領域にあった 空気 9 1 5は流路 9 0 1中に押し出される。空気 9 1 5は流路 9 0 1中のバ ッファ 9 1 2の流動を堰き止める役割を果たし、スィツチが閉止した状態と なる。  When the trigger liquid is introduced into the pump 910 via the flow path 903 from the standby state shown in Fig. 11 (a), it leaks into the hydrophobic area 906 and is stored in the hydrophilic area 904 The buffer is brought into contact with the liquid surface of the hydrophobic region 906. Then, the buffer stored in the hydrophilic region 904 moves to the channel 901 side, and is sucked into the columnar body forming region 908 by capillary force. Then, the air 915 existing in this area is pushed out into the flow path 901. The air 915 plays a role of blocking the flow of the buffer 912 in the flow path 901, and the switch is closed.
第 7の実施の形態  Seventh embodiment
本実施形態では、 可逆的なスィッチに関するものである。 可逆的なスイツ チとは、 流路の開通、 閉止を繰り返し可逆的に行うことのできるスィッチを いう。 図 1 2 ( a ) は本実施形態に係るスィッチの概略構造を示す。 このス ィツチは、主流路 9 2 4側壁に第一のトリガ一流路 9 2 0および第二のトリ ガー流路 9 2 6が連通して設けられている。 これらの流路の交差する位置に 疎水領域 9 2 2が設けられている。 また、 図示したように各流路に疎水領域 9 3 0が設けられている。 これらの疎水領域は、 図 8に示したものと同様の 構成を有し、円形状の疎水領域が所定のパターンで周期的に形成された領域 となっている。 主流路 9 2 4中、 疎水領域 9 2 2よりも上流側 (紙面左側) に、 バッファ 9 2 7が留まっている。  This embodiment relates to a reversible switch. A reversible switch is a switch that can open and close a flow channel repeatedly and reversibly. FIG. 12A shows a schematic structure of the switch according to the present embodiment. In this switch, a first trigger one flow path 920 and a second trigger flow path 926 are provided in communication with a side wall of a main flow path 924. A hydrophobic region 922 is provided at a position where these flow paths intersect. Further, as shown in the figure, a hydrophobic region 930 is provided in each channel. These hydrophobic regions have a configuration similar to that shown in FIG. 8, and are regions in which circular hydrophobic regions are periodically formed in a predetermined pattern. In the main flow path 9224, a buffer 927 remains upstream of the hydrophobic area 922 (left side on the paper).
図 1 2 ( b ) は、 第一のトリガー流路 9 2 0にトリガー液が導入された状 態を示す。 このとき、 疎水領域 9 2 2において、 ノ ッファ 9 2 7とトリガ一 液とが接触し、 これらが連続相を生成する。 すると、 図中右方向の下流側に バッファ 9 2 7が流動する。 すなわち、 スィッチが開状態となる。 FIG. 12 (b) shows a state in which the trigger liquid has been introduced into the first trigger channel 920. At this time, in the hydrophobic region 9222, the knocker 9227 and the trigger liquid come into contact, and these form a continuous phase. Then, on the downstream side in the right direction in the figure Buffer 9 27 flows. That is, the switch is opened.
次に、 図 1 2 ( c ) のように第二のトリガー流路 9 2 6内の空気を加圧す ることにより、 気泡 9 2 8が押し出されて導入される。 気泡 9 2 8は強い疎 水性であるので、 スィッチが閉状態となり、 バッファ 9 2 7の移動が停止す る。  Next, as shown in FIG. 12 (c), by pressurizing the air in the second trigger channel 926, the bubbles 928 are pushed out and introduced. Since the bubbles 928 are strongly hydrophobic, the switch is closed and the movement of the buffer 927 stops.
第二のトリガ一流路 9 2 6への加圧を止め、バッファ 9 2 7の移動が停止 すると、 再び図 1 2 ( a ) の状態に戻る。 その後、 さらに図 1 2 ( b ) の如 くスィッチを開状態にすることができる。 すなわち、 スィッチの可逆動作が 可能となる。  When the pressurization of the second trigger one flow path 9 26 is stopped and the movement of the buffer 9 27 stops, the state returns to the state shown in FIG. 12 (a) again. Thereafter, the switch can be further opened as shown in FIG. 12 (b). That is, reversible operation of the switch becomes possible.
第 8の実施の形態  Eighth embodiment
本実施形態は、 図 1 3 ( a ) に示すように、 流路 1 1 0 2を移動する液体 が、副流路 1 1 0 0を経由して上流側にあるスィツチ 1 1 0 1にフィードバ ックして作用し、流路 1 1 0 2を遮断する構造のスィツチに関するものであ る。  In this embodiment, as shown in FIG. 13 (a), the liquid moving in the flow path 1102 is fed back to the switch 1101 on the upstream side via the sub flow path 1100. The present invention relates to a switch having a structure that acts by locking and shuts off the flow path 1102.
このフィードバック型スィツチは、特定のチヤンバーが満たされたとき液 の流入を停止させるスィッチとして有効に利用できる。 たとえば、 図 6の装 置における装置において、サンプル定量管 5 3 0と分離用流路 5 4 0とが交 差する点に液体が到達したとき、さらなる液体の侵入を抑止するといつた利 用形態が可能である。  This feedback type switch can be effectively used as a switch for stopping the flow of liquid when a specific chamber is filled. For example, when the liquid reaches the point where the sample quantification tube 530 and the separation channel 540 cross each other in the apparatus in the apparatus shown in Fig. 6, it is assumed that further liquid intrusion is suppressed. Is possible.
図 1 3 ( b ) は、 こうしたフィードバック型の動作により、 流速の変化を 抑制する機構の一例を示す。 この機構においては、 基板 1 1 1 0中に流路 1 1 1 2が設けられている。 基板 1 1 1 0の上部は流路となっている。 流路 1 1 1 2には鉱物油等の不活性な疎水性液体が満たされている。  Figure 13 (b) shows an example of a mechanism that suppresses changes in flow velocity by such a feedback-type operation. In this mechanism, a flow path 111 is provided in a substrate 110. The upper part of the substrate 110 is a flow path. The channel 1 1 1 2 is filled with an inert hydrophobic liquid such as mineral oil.
以下、 図中、 左から右に向かう方向に液体が流動している場合を例に挙げ て説明する。 この疎水性液体は流路 1 1 1 2から少量はみ出た状態となって おり、 上流側に液滴 1 1 1 6、 下流側に液滴 1 1 1 4が形成される。 流路の 上流側と下流側とで等圧の場合、 これらの液滴は同じ大きさとなるが、 流速 が大きくなる等により下流側で流路内圧が高まった場合、液滴 1 1 1 4が小 さくなり、その分、液滴 1 1 1 6が大きくなり液滴 1 1 1 8のようになる(図 1 3 (c))。 この結果、 流路の実効断面積が小さくなつて流量が減少する。 これにより、 下流側の圧力が増加すると、 再び図 1 3 (b) の状態に戻り、 正常な流動状態となる。 こうして流路の各場所における流速のばらつきを抑 制することができる。 Hereinafter, a case where the liquid flows from left to right in the drawing will be described as an example. This hydrophobic liquid is in a state of protruding a small amount from the flow channel 1 1 1 2, and a droplet 1 1 16 is formed on the upstream side and a droplet 1 1 1 4 is formed on the downstream side. When the pressure is equal between the upstream side and the downstream side of the flow path, these droplets have the same size.However, when the internal pressure of the flow path increases on the downstream side due to an increase in flow velocity or the like, the droplets 1 1 1 4 small As a result, the size of the droplet 1 1 16 increases and the droplet 1 1 18 becomes as shown in FIG. 13 (c). As a result, the flow rate decreases as the effective area of the flow path decreases. As a result, when the pressure on the downstream side increases, the state returns to the state shown in Fig. 13 (b), and the flow becomes normal. In this way, it is possible to suppress variations in the flow velocity in each location of the flow path.
以上の動作は、 図中、 右から左に向かう方向に液体が流動している場合に おいても同様にあてはまる。 この場合、 下流側の流量が小さくなり圧力が減 少すると、上流側の流路の実効断面積が大きくなつて流量が増大することに なる。  The above operation also applies to the case where the liquid flows from right to left in the figure. In this case, if the flow rate on the downstream side decreases and the pressure decreases, the effective cross-sectional area of the upstream flow path increases and the flow rate increases.
第 9の実施の形態  Ninth embodiment
本実施形態は、 マイクロチップにクロックラインを設け、 これに基づいて チップ上の流路における液体の流動を制御するものである。 ここでは複数試 料を E S I — MS (エレクトロスプレーイオン化質量分析; electrospray ionization mass spectrometry) でィンジェクションする場合を例に挙げて 説明する。 ここで複数試料とは、 異なる種類のタンパク質、 例えば二次元電 気泳動で分取された各スポッ卜に含まれるタンパク質やべプチドを、アルキ ル化、 酵素消化、 脱塩した後の試料をいう。  In the present embodiment, a clock line is provided on a microchip, and the flow of liquid in a flow path on the chip is controlled based on the clock line. Here, an example is described in which multiple samples are injected by ESI-MS (electrospray ionization mass spectrometry). Here, the term “multiple samples” refers to samples obtained by alkylating, enzymatically digesting, and desalting proteins of different types, for example, proteins and peptides contained in spots collected by two-dimensional electrophoresis. .
図 14は本実施形態に係るスィッチを配設したチップの構造を示す。図 1 4 (a) はこのチップの上面図である。 第一の処理済み液 1 2 04の通る流 路 1 203と、第二の処理済み液 1 20 5の通る流路 1 2 0 3とが並行して 形成されている。 これらと直交する方向にクロック流路 1 20 1が設けられ ている。 これらは、 図 14 (b) に示すように、 多層の流路構造となってい る。 図 14 (b) はこのチップの断面図である。 主流路用基板 1 2 2 0およ びクロック流路用基板 1 2 1 0が張り合わされた構造を有する。主流路用基 板 1 220の表面には主流路 1 20 3が形成され、クロック流路用基板 1 2 1 0の表面にはクロック流路 1 20 1が形成されている。 これらの流路は、 制御用流路 1 2 1 2により接続されている。 主流路 1 20 3には、 スィツチ 1 2 0 7が設けられている。 図 1 4 ( a ) に戻り、 クロック流路 1 2 0 1に導入されたクロック用流体 は、 時間遅れチャンバ 1 2 0 2によって流動が制御された後、 制御用流路 1 2 1 2を経由してスィツチ 1 2 0 7に到達する。すると流路 1 2 0 3が開状 態となり第一の処理済み液 1 2 0 4が下流側に移動し、 E S I— M Sのイン ジェク夕に導かれる。 FIG. 14 shows the structure of a chip provided with the switch according to the present embodiment. FIG. 14 (a) is a top view of the chip. A flow path 1203 through which the first processed liquid 1204 passes and a flow path 1203 through which the second processed liquid 1205 passes are formed in parallel. A clock channel 1 201 is provided in a direction orthogonal to these. These have a multilayer flow path structure as shown in FIG. 14 (b). FIG. 14B is a sectional view of the chip. It has a structure in which a main flow path substrate 122 and a clock flow path substrate 120 are laminated. A main flow path 1203 is formed on the surface of the main flow path substrate 1220, and a clock flow path 1201 is formed on the surface of the clock flow path substrate 1210. These flow paths are connected by a control flow path 122. The main flow path 1203 is provided with a switch 127. Returning to Fig. 14 (a), the flow of the clock fluid introduced into the clock channel 1 201 is controlled by the time delay chamber 1 202, and then passes through the control channel 1 2 1 2 Then you reach Switch 127. Then, the flow path 123 is opened, and the first treated liquid 1224 moves to the downstream side, and is guided to the ESI-MS injector.
その後、 クロック用流体はクロック流路 1 2 0 1下流側に移動し、 別の時 間遅れチャンバを経た後、 スィッチ 1 2 0 8に到達する。 このスィツチ 1 2 0 8は、 トリガーが到達すると流路が閉止するタイプのスィツチであるため、 クロック用流体がトリガーとなって流路 1 2 0 3が閉止する。 その後、 第二 の処理済み液 1 2 0 5の通る流路 1 2 0 3に対しても同様に作用し、第二の 処理済み液 1 2 0 5は下流側に移動し、 E S I _ M Sのィンジェクタに導か れる。  Thereafter, the clock fluid moves to the downstream side of the clock channel 1221, and after another time delay chamber, reaches the switch 122. Since this switch 122 is a switch of a type in which a flow path is closed when a trigger arrives, a clock fluid serves as a trigger to close the flow path 123. Thereafter, the same applies to the flow path 1203 through which the second treated liquid 1205 passes, and the second treated liquid 1205 moves to the downstream side, and the ESI_MS It is led to the injector.
クロック流路 1 2 0 1におけるクロック用流体の流動は、 あらかじめ、 流 路中の任意の位置に到達する所用時間が正確に再現されるようになってい る。 このため、 このクロック流路の利用により、 チップ上で任意の処理を時 間制御性良く実行することが可能となる。  In the flow of the clock fluid in the clock channel 1221, the required time to reach an arbitrary position in the channel is accurately reproduced in advance. For this reason, by using this clock channel, it is possible to execute arbitrary processing on the chip with good time controllability.
第 1 0の実施の形態  10th embodiment
本実施形態では、 疎水領域によって遮断された流路に対し、 振動を与えて 流路を開通するものである。 図 1 5 ( a ) は、 このスィッチの構造を示す。 図中、 主流路 1 0 1中に疎水領域からなる堰き止め部 1 1 0が設けられ、 こ の部分で液体試料 1 0 4が堰き止められている。堰き止め部 1 1 0以外の部 分は、 親水性の基板表面が露出している。 堰き止め部 1 1 0の構造は、 図 8 に示したものと同様である。  In the present embodiment, vibration is applied to the flow path blocked by the hydrophobic region to open the flow path. Figure 15 (a) shows the structure of this switch. In the figure, a damming portion 110 made of a hydrophobic region is provided in a main flow path 101, and a liquid sample 104 is dammed in this portion. The hydrophilic substrate surface is exposed in portions other than the damming portion 110. The structure of the blocking unit 110 is the same as that shown in FIG.
この状態で、 このスィツチの形成されたマイクロチップ全体に振動を与え る。 すると、 堰き止め部 1 1 0中に保持されていた液体試料 1 0 4が堰き止 め部 1 1 0を越え下流側に移動し、 流路が開通状態となる。  In this state, vibration is applied to the entire microchip on which the switch is formed. Then, the liquid sample 104 held in the blocking unit 110 moves to the downstream side beyond the blocking unit 110, and the flow path is opened.
振動を与える方法としては様々な方法を用いることができる。図 1 8はそ の一例である。 この図は図 1 5 ( a ) のスィッチを横方向から見た断面図で ある。 流路 1 0 1にふた 1 4 1が設けられ、 ふた 1 4 1に、 振動付与手段と して突起 1 4 0が設けられている。 この突起 1 4 0を折り折損すると流路 1 0 1に振動が付与されスィッチが開通する。 Various methods can be used as a method of giving vibration. Figure 18 is an example. This figure is a cross-sectional view of the switch in Fig. 15 (a) viewed from the side. is there. A lid 141 is provided in the flow path 101, and a projection 140 is provided in the lid 141 as vibration applying means. When the protrusion 140 is broken, vibration is applied to the flow path 101 and the switch is opened.
図 1 9、 図 2 0はスィッチを開始する方法の別な例である。  FIG. 19 and FIG. 20 show another example of a method of starting a switch.
図 1 9は試料の滴下によりスィッチが開状態となる。 基板 1 5 5、 ふた 1 5 6の間に流路 1 5 9が形成されている。保水領域 1 5 2と吸水領域 1 5 4 の間に疎水領域 1 5 3が介在している。保水領域 1 5 2には水溶液が貯蔵さ れ、 適当な圧力がかけられている。 疎水領域 1 5 3により堰き止められてい る。 疎水領域 1 5 3に血液等の親水性の試料 1 5 0を滴下することにより、 保水領域 1 5 2と吸水領域 1 5 4が連続し、図中左から右へ流動が開始する。 図 2 0は移動部材を用いた例である。保水領域 1 5 2と吸水領域 1 5 4の 間に疎水領域 1 5 3が介在している。保水領域 1 5 2には水溶液が貯蔵され ており疎水領域 1 5 3により堰き止められている。表面親水性の磁性体 1 6 0は、 はじめは保水領域 1 5 2に位置しているが、 これを外部から磁石によ り操作することによって保水領域 1 5 2および吸水領域 1 5 4に跨る位置 に移動させると、磁性体 1 6 0の親水表面を介して保水領域 1 5 2と吸水領 域 1 5 4が連続し、 図中上から下へ流動が開始する。 本例では、 磁性体 1 6 0の直径を疎水領域 1 5 3の幅以上の大きさとしている。 これにより、 スィ ツチが良好に動作する。  In Fig. 19, the switch is opened by dropping the sample. A flow path 159 is formed between the substrate 155 and the lid 156. A hydrophobic region 153 is interposed between the water retaining region 152 and the water absorbing region 154. An aqueous solution is stored in the water retaining area 152 and an appropriate pressure is applied. Blocked by hydrophobic area 15 3. By dropping a hydrophilic sample 150 such as blood onto the hydrophobic region 153, the water retaining region 152 and the water absorbing region 154 continue, and the flow starts from left to right in the figure. FIG. 20 shows an example using a moving member. A hydrophobic region 153 is interposed between the water retaining region 152 and the water absorbing region 154. An aqueous solution is stored in the water retention area 152 and is blocked by the hydrophobic area 1553. The surface-hydrophilic magnetic material 160 is initially located in the water retention area 152, but it is straddled over the water retention area 152 and water absorption area 154 by externally operating this with a magnet. When it is moved to the position, the water retention area 152 and the water absorption area 154 continue through the hydrophilic surface of the magnetic material 160, and the flow starts from top to bottom in the figure. In this example, the diameter of the magnetic body 160 is set to be equal to or larger than the width of the hydrophobic region 153. This allows the switch to operate satisfactorily.
第 1 1の実施の形態  Eleventh embodiment
図 1 6は質量分析装置の構成を示す概略図である。 図 1 6において、 試料 台上に乾燥試料が設置される。 そして、 真空下で乾燥試料に波長 3 3 7 n m の窒素ガスレーザ一が照射される。 すると、 乾燥試料はマトリックスととも に蒸発する。 試料台は電極となっており、 電圧を印可することにより、 気化 した試料は真空中を飛行し、 リフレクター検知器、 リフレクタ一、 およびリ ニァ一検知器を含む検出部において検出される。  FIG. 16 is a schematic diagram showing the configuration of the mass spectrometer. In Fig. 16, the dried sample is placed on the sample stage. Then, the dried sample is irradiated with a nitrogen gas laser having a wavelength of 337 nm under vacuum. The dried sample then evaporates with the matrix. The sample stage is an electrode, and when a voltage is applied, the vaporized sample flies in a vacuum and is detected by a detection unit including a reflector detector, a reflector, and a linear detector.
図 1 7は本実施形態の乾燥装置を含む質量分析システムのプロック図で ある。 このシステムは、 試料 1 0 0 1について、 夾雑物をある程度除去する 精製 1 0 0 2、 不要成分 1 0 Q 4を除去する分離 1 0 0 3、 分離した試料の 前処理 1 0 0 5、 前処理後の試料の乾燥 1 0 0 6、 の各ステップを実行する 手段を備えている。 これらの各手段のうち一部または全部を一または二以上 のマイクロチップ 1 0 0 8上に搭載することができる。試料をマイクロチッ プ 1 0 0 8上で連続的に処理することにより、微量の成分についても損出が 少ない方法で効率よく確実に同定を行うことが可能となる。 FIG. 17 is a block diagram of a mass spectrometry system including the drying device of the present embodiment. This system removes some impurities from sample 1001 Perform the following steps: purification 1002, separation 1000 to remove unnecessary components 1003, pretreatment of the separated sample 1005, and drying of the sample after pretreatment 1006. Means. Some or all of these means can be mounted on one or more microchips 108. By continuously processing the sample on the microchip 108, it is possible to identify even a small amount of component efficiently and reliably by a method with less loss.
上記実施形態において、堰き止め部はトリガー流路と近接した位置に有る ことが好ましい。 具体的には、 主流路およびトリガ一流路の各中心線の交叉 する点を交叉点と定義すると、 交差点と疎水性処理部との距離は、 トリガー 流路の幅の 1 . 5倍以下とすることが好ましく、 トリガー流路の幅以下とす ることがより好ましい。 こうすることにより、 安定したスィッチ動作を実現 することができる。  In the above embodiment, it is preferable that the damming portion is located at a position close to the trigger channel. Specifically, if the point where the center line of the main flow path and the center line of the trigger flow path intersect is defined as the crossing point, the distance between the intersection and the hydrophobic processing section is 1.5 times or less the width of the trigger flow path. It is preferable that the width be equal to or less than the width of the trigger channel. By doing so, a stable switch operation can be realized.
(実施例 1 )  (Example 1)
本実施例は、 液体スィツチのオン動作を確認したものである。  In this embodiment, the ON operation of the liquid switch is confirmed.
本実施例では、 さらに、 液体スィッチが流路用の溝を掘ることなく、 疎水 性インクで描かれた流路パターンで実現できることを確認したものでもあ る。  In this example, it was further confirmed that the liquid switch can be realized by a flow path pattern drawn with hydrophobic ink without digging a groove for the flow path.
図 2 1にチップの構造を示す。 (A ) は平面構造を示す写真、 (B ) はその 断面図である。 親水性のスライドグラス 8 0 0 (白縁磨フロストスライドグ ラス p r e— c l e a n e d、 松波硝子工業株式会社、 水の接触角は約 7 度) を基板として、 その上にガラス用の油性ペン (Y Y F 1、 超頑固しつか りマーカ一、 ゼブラ株式会社、 水の接触角は約 7 0度、 もしくは、 X 1 0 0 W— S D、 ペンテルホワイト、 ぺんてる株式会社、 水のとの接触角は約 1 0 0度) を用いて、 幅 5 mmの主流路 8 0 5部分と、 幅 1 mmのトリガー流路 8 0 6部分と、 疎水性処理部 8 0 8を含む流路パターン 8 0 9を描画した。 流路部分は、その外周を幅 l mm〜 2 mmのペン先でなぞることで実現し た。水は疎水性の領域から排除されるため流路パターン 8 0 9の線と線の間 だけを流れる。 主流路 8 0 5内の液体を停止させる疎水性処理部 8 0 8は、 ペン先を削ったペンで幅約 80 の線を引くことで実現した。 Figure 21 shows the structure of the chip. (A) is a photograph showing a planar structure, and (B) is a cross-sectional view thereof. A hydrophilic slide glass 800 (white polished frost slide glass pre-cleaned, Matsunami Glass Co., Ltd., water contact angle is about 7 degrees) is used as a substrate, and an oil-based pen for glass (YYF 1 , Super stubborn marker one, Zebra Corporation, water contact angle is about 70 degrees, or X100 W—SD, Pentel White, Pentel Corporation, water contact angle is about 10 0 °), a flow path pattern 809 including a 5 mm wide main flow path 805 part, a 1 mm width trigger flow path 806 part, and a hydrophobic processing part 808 was drawn. . The flow path was realized by tracing the outer circumference with a pen tip having a width of l mm to 2 mm. Since water is excluded from the hydrophobic region, it flows only between the lines of the flow path pattern 809. The hydrophobic processing section 8 08 that stops the liquid in the main flow path 8 05 This was achieved by drawing a line approximately 80 in width with a pen with a sharpened tip.
次にスぺ一サ一として、 厚さ約 0. 3mmの両面テープ 8 0 1 (株式会社二 トムズ) を貼付し、 その上に疎水性表面を持つカバーガラス 8 0 4 (Matsunami micro cover glass thickness 0.17-0.25 風 silicone coated 20X20匪、 松波硝子工業株式会社、 水との接触角は約 8 5度) を貼付した。 これによつて生じた深さ約 0. 3 mmの縦方向の隙間 8 0 3と、 疎水性の流 路パターン 8 0 9に挟まれた横方向の隙間によって、主流路 80 5とトリガ 一流路 8 06が形成される。 Next, as a supplier, a double-sided tape 800 (Niitoms Co., Ltd.) with a thickness of about 0.3 mm is applied, and a cover glass with a hydrophobic surface is placed on top of it. 0.17-0.25 style silicone coated 20X20 marauder, Matsunami Glass Co., Ltd., contact angle with water is about 85 degrees). The main flow path 805 and the trigger flow path are formed by the vertical gap 803 with a depth of about 0.3 mm created by this and the horizontal gap sandwiched by the hydrophobic flow path patterns 809. 8 06 is formed.
このチップを水平なテーブルに設置して用いた。 図 22は、 このチップの スィッチ動作を示す連続写真である。 図 22 (A) は、 初期状態である。 図 2 2 (B) は、 主流路の右端から 1 0倍に希釈した黒ィンク 807 (S P S — 400 # 1、 プラチナ万年筆株式会社) を導入した後の写真である。 黒ィ ンク 807は毛細管効果で主流路 80 5に自動的に進入した後、疎水性処理 部 808にて停止し、 その状態を保った. 2分後、 トリガー流路 8 0 6の端 に水 8 1 0 (水道水) を導入した。 図 22 (C) は、 その直後の写真である。 水 8 1 0は、 毛細管効果でトリガー流路 80 6に急速に進入し、 次の瞬間そ の液面は、疎水性処理部 808で停止していた黒インク 8 0 7の液面と融合 した。 これにより液面が疎水性処理部 8 08をまたぎ、 黒インク 8 0 7は主 流路 8 0 5を左側へと進行した (図 22 (D))。 その間、 主流路 8 0 5内の 黒インク 8 0 7がトリガ一流路 806方向に逆流したり、 トリガー流路 80 6内の水 8 1 0が主流路 8 0 5方向に、 さらに流れ出す現象は観察されなか つた。 これはトリガー流路 8 0 6の幅が主流路 8 0 5の幅と比較して狭く、 流路抵抗が大きいためと考えられる。  This chip was placed on a horizontal table and used. FIG. 22 is a series of photographs showing the switching operation of this chip. Fig. 22 (A) shows the initial state. Figure 22 (B) is a photograph after introducing the black ink 807 (SPS-400 # 1, Platinum Fountain Pen) diluted 10 times from the right end of the main channel. The black ink 807 automatically entered the main flow path 805 due to the capillary effect, stopped at the hydrophobic processing section 808, and maintained that state. 8 10 (tap water) was introduced. Figure 22 (C) is the photograph immediately after. The water 810 rapidly enters the trigger channel 806 due to the capillary effect, and at the next moment its liquid level merges with the liquid level of the black ink 807 stopped at the hydrophobic processing section 808. . As a result, the liquid surface straddled the hydrophobic processing section 808, and the black ink 807 proceeded to the left in the main flow path 805 (FIG. 22 (D)). In the meantime, observe the phenomenon that the black ink 807 in the main channel 805 flows back in the direction of the trigger channel 806, and the water 810 in the trigger channel 806 further flows out in the direction of the main channel 805. Not done. This is probably because the width of the trigger channel 806 is narrower than the width of the main channel 805, and the channel resistance is large.
以上の結果から、 幅 5mmというマクロサイズの主流路 80 5でも、 それ より細いトリガー流路 80 6によって開通できること、 さらにスィッチを構 成する流路は、 溝を掘ることなく、 親水性の表面に疎水性のインクで縁取り 描画するだけで実現できることが示された。  From the above results, the macro-sized main flow path 805 with a width of 5 mm can be opened by the narrower trigger flow path 806. It was shown that this can be achieved simply by drawing a border with hydrophobic ink.
(実施例 2) 本実施例は、 1 0 /imから 1 0 0 程度のさらに細い流路で液体スィッ チのオン動作を確認したものである。 さらに、 本実施例の液体スィッチはフ ォトリソグラフィ一によって試作されたものであり、数センチ角のチップ上 に、 多数の液体スィツチを含む流路系が集積可能なことを意味する。 (Example 2) In the present embodiment, the ON operation of the liquid switch was confirmed in a narrower flow path of about 100 / im to about 100. Further, the liquid switch of the present embodiment is a prototype produced by photolithography, which means that a channel system including a large number of liquid switches can be integrated on a chip of several centimeters square.
図 23は試作した液体スィッチの構造を示す平面図である。 T字状に見え るものは、 後述する方法でシリコン基板 9 00上に掘られた溝である。 左右 に伸びる主流路 9 0 5と、 直角に交わるトリガ一流路 90 6、 その交叉点を はさんで主流路 9 0 5の右側には疎水性処理部 9 08が設けられている。流 路の太さと、 疎水性処理部 9 0 8の幅や設置場所、 そして主流路へ液体を導 入する方向に応じて 4タイプを設けた。 それぞれのタイプは、 図 23に付し た英字記号 (A) 〜 (D) で参照する。  FIG. 23 is a plan view showing the structure of a prototype liquid switch. What looks like a T-shape is a groove dug on the silicon substrate 900 by a method described later. A main flow path 905 extending to the left and right, a trigger single flow path 906 intersecting at right angles, and a hydrophobic processing section 908 is provided on the right side of the main flow path 905 across the intersection. Four types were provided according to the thickness of the channel, the width and location of the hydrophobic treatment section 908, and the direction in which the liquid was introduced into the main channel. Each type is referred to by the alphabetic symbols (A) to (D) attached in Fig. 23.
タイプ (A) は、 1 0 0 mの主流路と 5 0 mのトリガ一流路を設け、 対照として疎水性部 9 0 8を設けたのと反対の左側から液体を導入するも の (タイプ (B)、 (C)、 (D)、 (E) では、 液体は、 疎水性処理部 9 0 8の ある右側から導入する)。  In the type (A), a main flow path of 100 m and a trigger flow path of 50 m are provided, and liquid is introduced from the left side opposite to the hydrophobic part 908 as a control (type ( In B), (C), (D), and (E), the liquid is introduced from the right side with the hydrophobic treatment section 908).
タイプ (B) は、 1 00 mの主流路と 5 0 mのトリガ一流路を設け、 交 叉部の直前に一部欠けのある幅 5 imの疎水性部 9 0 8を設けたものであ る。 疎水性部 9 0 8は、 透明なので見ることはできないが、 図 2 3の平面図 に点線で示した。 Type (B) has a main flow path of 100 m and a trigger flow path of 50 m, and a hydrophobic part 908 with a width of 5 im, which is partially missing, is provided immediately before the intersection. You. The hydrophobic portion 908 cannot be seen because it is transparent, but is shown by a dotted line in the plan view of FIG.
タイプ (C) は、 5 0 zmの主流路と 5 0 mのトリガー流路を設け、 交叉 部の直前に一部欠けのある幅 5 zmの疎水性部 9 08を設けたもの、 タイプ (D) は、 1 00 mの主流路と 5 0 mのトリガ一流路を設け、 交 又部分から離れた位置に幅 5 mの疎水性部 90 8を設けたものである。 なお、 図には示さなかったが、 各流路の端には 1ミリメートル角の液溜を流 路と同時にエッチングした。 Type (C) has a 50 zm main flow path and a 50 m trigger flow path, and has a 5 zm wide hydrophobic part 908 with a partial cut-out just before the intersection. Type (D ) Has a main flow path of 100 m and a trigger flow path of 50 m, and a hydrophobic part 908 having a width of 5 m is provided at a position away from the intersection. Although not shown in the figure, a 1 mm square liquid reservoir was etched at the end of each channel at the same time as the channels.
これらの液体スィッチは、 次のような工程で試作した。 These liquid switches were prototyped by the following process.
[液体スィツチの試作]  [Prototype of liquid switch]
( 1) 流路部分のフォトリソグラフィ一とゥエツトエッチング 清浄な ( 1 1 0) シリコン基板の全面を熱酸化して、 20 00オングスト ロームの熱酸化膜を形成する。 次に、 フォトレジスト (S 1 8 1 8、 S h i 1 e yファーイースト株式会社) を塗布し、 前記タイプ (A) 〜 (D) の 液体スィツチの流路パターンが描かれた石英クロムマスクを使って露光 ·現 像することにより、流路パターン部分のフォトレジストを除去し酸化膜を露 出させる。露出した酸化膜をバッファ一ドフッ酸( 1 6バッファードフッ酸、 森田化学工業株式会社) にて除去し、 シリコン面を露出させる。 つづいて基 板に残ったフォ卜レジストを、アセトンとエタノールで洗浄して完全に除去 し、 水洗'乾燥の後、 9 0°Cに加温した 2 5 %TMAHで約 20分間エッチ ングすることで、流路パターン部分が約 20 tmエッチングされたシリコン 基板を得た。 これをバッファードフッ酸に浸漬して、 残った熱酸化膜を除去 した。 (1) Photolithography and channel etching of the channel The entire surface of the clean (110) silicon substrate is thermally oxidized to form a thermal oxide film of 2000 angstroms. Next, a photoresist (S1818, Shi1ey Far East Co., Ltd.) is applied, and a quartz chrome mask on which the flow patterns of the liquid switches of the types (A) to (D) are drawn is used. Exposure and image formation removes the photoresist in the flow path pattern and exposes the oxide film. The exposed oxide film is removed with buffered hydrofluoric acid (16 buffered hydrofluoric acid, Morita Chemical Co., Ltd.) to expose the silicon surface. Subsequently, the photoresist remaining on the substrate is completely removed by washing with acetone and ethanol, washed with water and dried, and then etched with 25% TMAH heated to 90 ° C for about 20 minutes. Thus, a silicon substrate was obtained in which the flow path pattern portion was etched by about 20 tm. This was immersed in buffered hydrofluoric acid to remove the remaining thermal oxide film.
なお、 主流路 90 5およびは、 マスク上では幅 1 00 mだがエッチング 後、 1 0 %〜 2 0 %ほど拡幅する。 トリガ一流路も同様である。  The main flow channel 905 and the width of the main flow channel 905 are 100 m on the mask, but widen by about 10% to 20% after etching. The same applies to one trigger channel.
(2) シリコン基板の化学酸化  (2) Chemical oxidation of silicon substrate
この流路パターンがエッチングされたシリコン基板の表面は、疎水性なの で、 これを親水性とするため 90°Cの濃硝酸に 40分間漬ける。 水洗後の基 板表面が親水性になっており、水が毛細管効果で流路を満たすことを確認す る。  Since the surface of the silicon substrate on which the flow path pattern has been etched is hydrophobic, it is immersed in concentrated nitric acid at 90 ° C for 40 minutes to make it hydrophilic. Confirm that the surface of the substrate after washing is hydrophilic, and that the water fills the flow channel by the capillary effect.
(3) 疎水性処理部 9 0 8の設置  (3) Installation of hydrophobic treatment section 908
上記化学酸化により表面が親水性となったシリコン基板に薄膜フォトレ ジスト (S 1 8 0 5、 S h i p 1 e yファーイースト株式会社) を直接滴下 し、 スピンコートする。 次いで疎水性処理部 9 0 8の部分が開口した石英ク ロムマスクを使って、 位置合わせをした後に露光 ·現像する。 これにより、 疎水性処理部 9 08だけ、 流路表面を露出させる。 この基板をステンレス容 器にいれ、 基板にかからないようにシラザンを滴下した後、 容器を密閉して 1 日放置する。気化したシラザンにより疎水性処理部 9 0 8に疎水性のシラ ザン膜が形成される(この膜は、アセトン'エタノール洗浄に抵抗性である)。 実験直前に、 この基板についている薄膜フォトレジストをアセトンとエタ ノールで除去し、 1 0分以上水洗した後、 エアガンで乾燥して用いた。 流路 上面にはフタは設けず開放状態とした。 A thin film photoresist (S185, Ship1ey Far East Co., Ltd.) is directly dropped onto the silicon substrate whose surface has become hydrophilic by the chemical oxidation, and spin-coated. Next, using a quartz chrome mask having an opening in the hydrophobic processing section 908, the alignment is performed, and then exposure and development are performed. As a result, only the hydrophobic processing section 908 exposes the flow channel surface. This substrate is placed in a stainless steel container, and silazane is dropped so as not to cover the substrate. Then, the container is sealed and left for one day. The vaporized silazane forms a hydrophobic silazane film in the hydrophobic treatment section 908 (this film is resistant to acetone-ethanol washing). Immediately before the experiment, the thin film photoresist on the substrate was removed with acetone and ethanol, washed with water for at least 10 minutes, and then dried using an air gun. The upper surface of the flow channel was left open without a lid.
[実験]  [Experiment]
上記の方法で試作した基板を、 金属顕微鏡のステージに水平に設置し、 こ れを 5倍、 あるいは 1 0倍の対物レンズと、 鏡筒につけた C CDを介してビ デォ (S o n y D i g i t a l H a n d y c um、 ソニー) で連続撮影 した。  The substrate fabricated by the above method was placed horizontally on the stage of a metallurgical microscope, and this was mounted on a 5 × or 10 × objective lens via a CCD attached to the lens barrel. igital H andy cum, Sony).
流路に入れる液体は、 界面活性剤 (NCW— 6 1 0A、 和光純薬工業株式 会社)を蒸留水で 1 0 0 0倍に希釈した無色溶液と、その無色溶液を用いて、 黒色インク (S P S— 400 # 1、 プラチナ万年筆株式会社) を 1 0倍に希 釈した色素液の 2種類を用意した。 希薄な界面活性剤を用いた理由は、 蒸留 水を用いた場合、 流路への流入速度が極めて遅く、 フタが無いため途中で流 路が乾燥してしまうという問題を避けるためである。進入速度が遅い理由は、 恐らく薄膜フォトレジストを塗布したことで基板表面の親水性が多少低下 したためと思われる。希薄な界面活性剤を用いることで、十分な流入速さ(約 The liquid to be introduced into the flow path is a colorless solution obtained by diluting a surfactant (NCW-610A, Wako Pure Chemical Industries, Ltd.) with distilled water by a factor of 100, and a black ink ( Two types of dye solutions were prepared by diluting SPS-400 # 1, Platinum Fountain Pen Co., Ltd. 10 times. The reason for using a dilute surfactant is to avoid the problem that when distilled water is used, the flow rate into the flow channel is extremely slow and the flow channel dries on the way because there is no lid. The reason why the approach speed is slow is probably that the application of the thin film photoresist slightly reduced the hydrophilicity of the substrate surface. By using a dilute surfactant, sufficient inflow speed (about
5 00 im,秒) が実現できた。 500 im, sec).
図 24は、 (A) タイプの液体スィッチに疎水性処理部 9 0 8と反対側の 左側から無色溶液を導入した後の連続写真である (対物レンズ 1 0倍)。 図 24の ( 1) から (6) のように、 無色溶液は主流路 9 0 5に自動的に進入 し、 交叉点を超えた後、 疎水性処理部 908で停止した。 この結果から疎水 性処理部 908は、 溶液を停止させる効果があることがわかる。  Fig. 24 is a series of photographs after introducing a colorless solution into the liquid switch (A) from the left side opposite to the hydrophobic processing part 908 (objective lens × 10). As shown in (1) to (6) in FIG. 24, the colorless solution automatically entered the main flow path 905 and stopped at the hydrophobic processing section 908 after crossing the intersection. From this result, it can be seen that the hydrophobic processing section 908 has an effect of stopping the solution.
図 2 5は、 タイプ (B) の液体スィッチの主流路 9 0 5に、 右側から色素 液を導入した後の連続写真である (対物レンズ 1 0倍)。 色素液は、 主流路 9 0 5に自動的に進入した (図 2 5 ( 1)) 後、 疎水性処理部 9 0 8部分で 主たる流れが停止した。色素液の一部が疎水性処理部 9 08と流路壁の隙間 をすり抜けて交叉点よりも先に達したが、 それ以上先には進行しなかった (図 2 5 (2))。 次に、 トリガー流路 9 06に無色液を導入したところ、 無 色液は自動的に進入して交叉点に到達した後、 その液面は、 先に停止してい た色素液の液面と融合した (図 2 5 ( 3 ) )。 その後、 色素液は疎水性処理部 9 0 8を超えて交叉点よりも左側の主流路 9 0 5を進行して行った。 Figure 25 shows a series of photographs after the dye solution was introduced into the main flow channel 905 of the type (B) liquid switch from the right side (objective lens × 10). After the dye liquid automatically entered the main flow channel 905 (FIG. 25 (1)), the main flow stopped at the hydrophobic processing section 908. A part of the dye solution passed through the gap between the hydrophobic processing part 908 and the flow path wall and reached the intersection, but did not proceed any further (Fig. 25 (2)). Next, when a colorless liquid was introduced into the trigger channel 906, After the color liquid automatically entered and reached the crossing point, the liquid level merged with the dye liquid level that had stopped earlier (Fig. 25 (3)). Thereafter, the dye solution was passed through the main flow channel 905 on the left side of the intersection beyond the hydrophobic processing portion 908.
この結果から 1 mm以下の流路でも、 トリガー流路 9 0 6からの液体供給に よって疎水性処理部 9 0 8の停止効果が失われ、主流路 9 0 5が開通するこ と、 すなわちオン動作が実現できることがわかる。 From this result, even in a flow path of 1 mm or less, the stopping effect of the hydrophobic processing section 908 is lost by the supply of the liquid from the trigger flow path 906, and the main flow path 905 is opened, that is, turned on. It turns out that the operation can be realized.
図 2 6は、 タイプ (C ) の液体スィッチの主流路 9 0 5に、 右側から色素 液を導入した後の連続写真である (対物レンズ 5倍)。 タイプ (B ) の場合 と同様に、 色素液は疎水性処理部 9 0 8で停止した (図 2 6 ( 1 ) )。 トリガ 一流路 9 0 6から無色液が供給されると、無色液と交 ¾点で停止していた液 面とが融合し (図 2 6 ( 4 ) )、 融合した液面は再び運動を始め、 主流路 9 0 5交叉点を超えて主流路 9 0 5の左側へと進行した。 但しこの場合、 主流路 9 0 5を進行したのは、 色素液でなく、 トリガー流路 9 0 6から供給された 無色液だった。 この結果から、 主流路 9 0 5の太さとトリガ一流路 9 0 6の 太さの関係、 供給される液体の量によっては、 スィッチ動作ができないこと がわかる。  Figure 26 shows a series of photographs after the dye solution was introduced into the main channel 905 of the type (C) liquid switch from the right side (5x objective lens). As in the case of type (B), the dye solution was stopped at the hydrophobic treatment section 908 (FIG. 26 (1)). Trigger When the colorless liquid is supplied from one channel 906, the colorless liquid merges with the liquid surface stopped at the intersection (Fig. 26 (4)), and the merged liquid surface starts moving again. Then, it proceeded to the left side of the main flow passage 905 beyond the intersection of the main flow passage 905. However, in this case, the colorless liquid supplied from the trigger flow path 906 was not the dye liquid that proceeded in the main flow path 905. From this result, it is understood that the switch operation cannot be performed depending on the relationship between the thickness of the main flow path 905 and the thickness of the trigger single flow path 906 and the amount of the supplied liquid.
図 2 7は、 タイプ (D ) の液体スィツチの主流路 9 0 5に、 右側から色素 を導入した後の連続写真である (対物レンズ 5倍)。 色素液は、 主流路 9 0 5を自動的に進入した後、 疎水性処理部 9 0 8で停止した (図 2 7 ( 1 ) )。 次に、 トリガー流路 9 0 6に無色液を導入したところ、 無色液が疎水性処理 部 9 0 8へ充分に導かれず、 スィッチ動作がやや不安定であった (図 2 7 ( 2 ) )。  Figure 27 shows a series of photographs after the dye was introduced into the main flow channel 905 of the type (D) liquid switch from the right side (5x objective lens). After the dye solution automatically entered the main flow path 905, it stopped at the hydrophobic processing section 908 (FIG. 27 (1)). Next, when a colorless liquid was introduced into the trigger channel 906, the colorless liquid was not sufficiently guided to the hydrophobic treatment section 908, and the switch operation was somewhat unstable (Fig. 27 (2)). .
以上の結果から、 疎水性処理部 9 0 8は、 交叉点から近接した場所に設け ることが好ましいことがわかる。主流路 9 0 5およびトリガ一流路 9 0 6の 各中心線の交叉する点を交叉点と定義すると、交差点と疎水性処理部 9 0 8 との距離は、 トリガ一流路 9 0 6の幅の 1 . 5倍以下とすることが好ましく、 トリガ一流路 9 0 6の幅以下とすることがより好ましい。 こうすることによ り、 安定したスィッチ動作を実現することができる。 上記例では、 (B ) お よび (C) では、 上記距離が 5 0 m, トリガ一流路 906の幅が 5 0〜6 0 m程度である。 (D) では、 上記距離が 1 0 0 /m、 トリガー流路 9 0 6の幅が 50〜 6 0 m程度である。 From the above results, it is understood that the hydrophobic processing section 908 is preferably provided at a location close to the intersection. If the point of intersection of each center line of the main flow path 900 and the trigger flow path 906 is defined as an intersection, the distance between the intersection and the hydrophobic processing section 908 is the width of the trigger flow path 906 The width is preferably 1.5 times or less, and more preferably the width of one trigger channel 906 or less. This makes it possible to realize a stable switch operation. In the above example, (B) In (C) and (C), the distance is 50 m, and the width of one trigger channel 906 is about 50 to 60 m. In (D), the distance is 100 / m, and the width of the trigger channel 906 is about 50 to 60 m.
以上を総合すると、液体スィツチのオン動作が 1 mm以下の細さの流路で も実現できること、 フォトリソグラフィー技術で製造できることから、 集積 化も可能なこと、 安定したオン動作を実現するためには、 交叉点と疎水性処 理部 9 08との位置、 溶液の界面活性を考慮することが好ましい。  Summarizing the above, the ON operation of the liquid switch can be realized even with a flow path as thin as 1 mm or less, and because it can be manufactured by photolithography technology, it can be integrated, and to realize stable ON operation It is preferable to consider the position of the intersection and the hydrophobic processing part 908, and the surface activity of the solution.

Claims

請 求 の 範 囲 The scope of the claims
1 . 第一の液体の通る流路と、 1. A flow path through which the first liquid passes;
前記流路中に設けられた、 前記第一の液体を堰き止める堰き止め部と、 前記堰き止め部またはその下流側の箇所で前記流路に連通し、前記堰き止 め部へ第二の液体を導く トリガー流路と、  A damming portion provided in the flow passage for damping the first liquid, and communicating with the flow passage at the damming portion or at a location downstream of the damming portion, and supplying the second liquid to the damming portion. Trigger channel and
を有することを特徴とする液体スィツチ。 A liquid switch comprising:
2 . 請求の範囲 1に記載の液体スィツチにおいて、  2. The liquid switch according to claim 1,
前記堰き止め部は、前記第一の液体を保持する部材を含むことを特徴とす る液体スィッチ。  The liquid switch, wherein the damming portion includes a member for holding the first liquid.
3 . 請求の範囲 2に記載の液体スィツチにおいて、  3. The liquid switch according to claim 2,
前記堰き止め部における流路単位体積あたりの流路表面積は、流路の他の 部分における流路単位体積あたりの流路表面積よりも大きいことを特徴と する液体スィツチ。  A liquid switch characterized in that a flow path surface area per unit volume of a flow path in the damming portion is larger than a flow path surface area per unit volume of a flow path in another part of the flow path.
4 . 請求の範囲 2に記載の液体スィッチにおいて、  4. The liquid switch according to claim 2,
前記第一の液体を保持する前記部材は、複数の粒子であることを特徴とす る液体スィツチ。  The liquid switch, wherein the member holding the first liquid is a plurality of particles.
5 . 請求の範囲 2に記載の液体スィッチにおいて、  5. The liquid switch according to claim 2,
前記第一の液体を保持する前記部材は、多孔質体であることを特徴とする 液体スィツチ。  The said member which holds the said 1st liquid is a porous body, The liquid switch characterized by the above-mentioned.
6 . 請求の範囲 2に記載の液体スィッチにおいて、  6. The liquid switch according to claim 2,
前記第一の液体を保持する前記部材は、離間して配置された複数の突起部 を含むことを特徴とする液体スィツチ。  The liquid switch according to claim 1, wherein the member holding the first liquid includes a plurality of protrusions arranged apart from each other.
7 . 請求の範囲 1に記載の液体スィッチにおいて、  7. The liquid switch according to claim 1,
前記堰き止め部は、前記第一の液体に対し疎液性を示す領域を含むことを 特徴とする液体スィツチ。  The liquid switch, wherein the damming portion includes a region showing lyophobicity to the first liquid.
8 . 請求の範囲 7に記載の液体スィッチにおいて、  8. The liquid switch according to claim 7, wherein:
前記流路における前記流路と前記トリガー流路の交差する箇所よりも下 流側に、前記第一の液体に対し疎液性を示す領域をさらに含むことを特徴と する液体スィッチ。 Below the intersection of the flow path and the trigger flow path in the flow path The liquid switch further comprising a region on the flow side that is lyophobic to the first liquid.
9 . 請求の範囲 1乃至 8いずれかに記載の液体スィツチにおいて、 前記トリガー流路に、 弁構造を備え、 所定量の第二の液体が導入されると 前記弁構造が作動し、前記トリガ一流路が閉止するように構成されたことを 特徴とする液体スィツチ。  9. The liquid switch according to any one of claims 1 to 8, wherein a valve structure is provided in the trigger flow path, and when a predetermined amount of a second liquid is introduced, the valve structure is activated, and the trigger first flow is activated. A liquid switch, characterized in that a passage is closed.
1 0 . 液体の通る流路と、 前記流路中に設けられた、 前記液体を堰き止 める堰き止め部とを有し、 前記堰き止め部は、 前記液体を保持する部材を含 むことを特徴とする液体スィツチ。  10. It has a flow path through which a liquid passes, and a blocking part provided in the flow path for blocking the liquid, wherein the blocking part includes a member for holding the liquid. A liquid switch characterized by the above.
1 1 . 請求の範囲 1 0に記載の液体スィッチにおいて、  1 1. In the liquid switch according to claim 10,
前記堰き止め部における流路単位体積あたりの流路表面積は、流路の他の 部分における流路単位体積あたりの流路表面積よりも大きいことを特徴と する液体スィツチ。  A liquid switch characterized in that a flow path surface area per unit volume of a flow path in the damming portion is larger than a flow path surface area per unit volume of a flow path in another part of the flow path.
1 2 . 請求の範囲 1 0または 1 1に記載の液体スィツチにおいて、 前記第一の液体を保持する前記部材は、複数の粒子であることを特徴とす る液体スィツチ。  12. The liquid switch according to claim 10 or 11, wherein the member holding the first liquid is a plurality of particles.
1 3 . 請求の範囲 1 0または 1 1に記載の液体スィツチにおいて、 前記第一の液体を保持する前記部材は、多孔質体であることを特徴とする 液体スィツチ。  13. The liquid switch according to claim 10 or 11, wherein the member holding the first liquid is a porous body.
1 4 . 請求の範囲 1 0または 1 1に記載の液体スィッチにおいて、 前記第一の液体を保持する前記部材は、離間して配置された複数の突起部 を含むことを特徴とする液体スィツチ。  14. The liquid switch according to claim 10 or 11, wherein the member holding the first liquid includes a plurality of spaced apart protrusions.
1 5 . 液体の通る流路と、 前記流路中に設けられた、 前記液体を堰き止 める堰き止め部とを有し、 前記堰き止め部は、 前記液体に対して疎液性の表 面を含むことを特徴とする液体スィッチ。  15. A flow path through which a liquid passes, and a damming portion provided in the flow passage for damping the liquid, wherein the damping portion has a lyophobic surface with respect to the liquid. A liquid switch comprising a surface.
1 6 . 請求の範囲 1 5に記載の液体スィツチにおいて、  1 6. The liquid switch according to claim 15, wherein:
前記流路中に、前記堰き止め部から前記堰き止め部以外の場所まで移動可 能に配置された移動部材をさらに有し、 前記移動部材は、 前記液体に対し親 液性を示す表面を有し、前記流路外部から前記移動部材の位置を調整できる ように構成されていることを特徴とする液体スィツチ。 The flow path further includes a moving member movably arranged from the damming portion to a location other than the damming portion, wherein the moving member has a A liquid switch having a surface exhibiting liquid properties, wherein the position of the moving member can be adjusted from outside the flow path.
1 7 . 請求の範囲 1 6に記載の液体スィツチにおいて、 外部から前記移 動部材の位置を調整する位置調整手段をさらに備え、前記移動部材および前 記位置調整手段のうち、一方が磁石であり他方が磁性体であることを特徴と する液体スィツチ。  17. The liquid switch according to claim 16, further comprising a position adjusting means for adjusting the position of the moving member from outside, wherein one of the moving member and the position adjusting means is a magnet. A liquid switch characterized in that the other is a magnetic material.
1 8 . 第一の液体の通る流路と、 前記流路に連通する副流路と、 前記副 流路に連通する室と、 前記室に連通し、 前記室に第二の液体を導入するトリ ガー流路と、 を備え、 前記室の内部に前記第一の液体に対して疎液性を示す 疎液性物質が貯蔵されており、前記トリガー流路から前記室へ第二の液体が 導入されたとき、前記室から前記流路へ前記疎液性物質が導入されるように 構成されたことを特徴とする液体スィツチ。  18. A flow path through which the first liquid passes, a sub flow path that communicates with the flow path, a chamber that communicates with the sub flow path, and a second liquid that is communicated with the chamber and that is introduced into the chamber. A trigger channel; and a lyophobic substance showing lyophobicity with respect to the first liquid is stored inside the chamber, and a second liquid is supplied from the trigger channel to the chamber. A liquid switch, wherein the lyophobic substance is introduced from the chamber to the flow path when introduced.
1 9 . 請求の範囲 1 8に記載の液体スィッチにおいて、 前記室は; 前記副流路に連通する第一の小室と、前記疎液性物質を貯蔵する第二の小室 と、前記第一および第二の小室の間に介在しこれらの小室を隔てる分離部と、 を備え、 前記トリガー流路が前記分離部に連通し、 前記トリガ一流路から第 二の液体が導入されたとき、前記第一の小室から前記第二の小室へ前記疎液 性物質が移動するように構成されたことを特徴とする液体スィツチ。  19. The liquid switch according to claim 18, wherein the chamber includes: a first chamber that communicates with the sub flow path; a second chamber that stores the lyophobic substance; A separation unit interposed between the second small chambers and separating these small chambers, wherein the trigger flow path communicates with the separation unit, and the second liquid is introduced from the one trigger flow path. A liquid switch, wherein the lyophobic substance moves from one small chamber to the second small chamber.
2 0 . 基板と、 該基板上に形成された試料の通る試料流路と、 該試料流 路中に設けられた試料分離部と、 を備え、 前記試料流路中に請求の範囲 1乃 至 1 9いずれかに記載の液体スィツチが配設されており、前記試料流路から 前記試料分離部への前記試料の供給が前記液体スィツチにより制御される ことを特徴とするマイクロチップ。  20. A substrate, a sample flow path through which a sample formed on the substrate passes, and a sample separation unit provided in the sample flow path, wherein the sample flow path is provided in the sample flow path. 19. A microchip, wherein the liquid switch according to any one of 19 is provided, wherein the supply of the sample from the sample flow path to the sample separation unit is controlled by the liquid switch.
2 1 . 基板と、 該基板上に形成された液体の通る液体流路と、 該液体流 路中に設けられた反応部と、 を備え、 前記液体流路中に請求の範囲 1乃至 1 9いずれかに記載の液体スィツチが配設されており、前記液体流路から前記 反応部への液体の供給が前記液体スィツチにより制御されることを特徴と するマイクロチップ。 21. A substrate, a liquid flow path formed on the substrate, through which a liquid passes, and a reaction section provided in the liquid flow path, wherein the liquid flow path is provided in the liquid flow path. A microchip, wherein the liquid switch according to any one of the above is disposed, and supply of a liquid from the liquid flow path to the reaction section is controlled by the liquid switch.
2 2 . 請求の範囲 2 1に記載のマイクロチップにおいて、 前記反応部に 連通し試薬の導入されるリザ一バをさらに備え、前記リザーバから前記反応 部に至る液体流路に前記液体スィツチが配設されており、前記リザ一バから 前記反応部への前記試薬の導入が前記液体スィツチにより制御されること を特徴とするマイクロチップ。 22. The microchip according to claim 21, further comprising a reservoir communicating with the reaction section and introducing a reagent, wherein the liquid switch is disposed in a liquid flow path from the reservoir to the reaction section. A microchip, wherein introduction of the reagent from the reservoir to the reaction section is controlled by the liquid switch.
2 3 . 請求の範囲 2 2に記載のマイクロチップにおいて、 前記試薬が酵素 消化液であることを特徴とするマイクロチップ。  23. The microchip according to claim 22, wherein the reagent is an enzyme digestion solution.
2 4 . 請求の範囲 2 3に記載のマイクロチップにおいて、 前記酵素消化液 がトリプシン消化液であることを特徴とするマイクロチップ。  24. The microchip according to claim 23, wherein the enzyme digestion solution is a trypsin digestion solution.
2 5 . 基板と、 該基板上に形成された液体の通る主流路と、 前記液体が前 記主流路の所定箇所に通過する時期を制御するクロック流路と、前記主流路 とクロック流路とに連通する制御流路と、 を備え、 前記制御流路に請求の範 囲 1乃至 1 9いずれかに記載の液体スィツチが配設されており、前記主流路 における前記液体の進行が前記液体スィツチにより制御されることを特徴 とするマイクロチップ。  25. A substrate, a main flow path through which liquid formed on the substrate passes, a clock flow path that controls a timing at which the liquid passes through a predetermined portion of the main flow path, a main flow path, and a clock flow path. And a control flow passage communicating with the main flow passage, wherein the control flow passage is provided with the liquid switch according to any one of claims 1 to 19, and the liquid flow in the main flow passage is controlled by the liquid switch. A microchip characterized by being controlled by a microchip.
2 6 . 生体試料を分子サイズまたは性状に応じて分離する分離手段と、 前 記分離手段により分離された試料に対し、酵素消化処理を含む前処理を行う 前処理手段と、 前処理された試料を乾燥させる乾燥手段と、 乾燥後の試料を 質量分析する質量分析手段と、  26. Separation means for separating a biological sample according to molecular size or properties, pretreatment means for performing pretreatment including enzymatic digestion treatment on the sample separated by the separation means, and pretreated sample Drying means for drying the sample, mass spectrometry means for mass analyzing the dried sample,
を備え、 前記分離手段は、 請求の範囲 2 0に記載のマイクロチップを含むこ とを特徴とする質量分析システム。 20. A mass spectrometry system comprising: the microchip according to claim 20;
2 7 . 生体試料を分子サイズまたは性状に応じて分離する分離手段と、 前 記分離手段により分離された試料に対し、酵素消化処理を含む前処理を行う 前処理手段と、 前処理された試料を乾燥させる乾燥手段と、 乾燥後の試料を 質量分析する質量分析手段と、  27. Separation means for separating a biological sample according to the molecular size or properties, pretreatment means for performing pretreatment including enzyme digestion treatment on the sample separated by the separation means, and pretreated sample Drying means for drying the sample, mass spectrometry means for mass analyzing the dried sample,
を備え、 前記前処理手段は、 請求の範囲 2 1乃至 2 4いずれかに記載のマイ クロチップを含むことを特徴とする質量分析システム。 A mass spectrometry system comprising: a microchip according to any one of claims 21 to 24;
2 8 . 生体試料を分子サイズまたは性状に応じて分離する分離手段と、 前 記分離手段により分離された試料に対し、酵素消化処理を含む前処理を行う 前処理手段と、 前処理された試料を乾燥させる乾燥手段と、 乾燥後の試料を 質量分析する質量分析手段と、 を備え、 前記分離手段、 前記前処理手段また は前記乾燥手段が、請求の範囲 2 5に記載のマイクロチップを含むことを特 徵とする質量分析システム。 28. Separation means for separating biological samples according to molecular size or properties A pretreatment means for performing a pretreatment including an enzyme digestion treatment on the sample separated by the separation means, a drying means for drying the pretreated sample, and a mass spectrometry means for performing mass analysis on the dried sample, 25. A mass spectrometry system, comprising: the separation unit, the pretreatment unit, or the drying unit including the microchip according to claim 25.
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